Radio-and chemo-protective compounds

ABSTRACT

The present disclosure relates to prodrugs, double prodrugs, derivatives and analogues of 3-(methylamino)-2-((methy-lamino)methyl)propane-1-thiol. Their use as radio- and chemo-protectors is also described.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority and benefit from U.S. ProvisionalApplication No. 63/021,937, filed May 8, 2020, the contents of which arehereby incorporated by reference in its entirety.

FIELD OF THE DISCLOSURE

The present disclosure relates to compounds that are radio- andchemo-protective agents, pharmaceutical compositions comprising thosecompounds, and methods of preventing or reducing a syndrome, toxicity,disease or condition associated with exposure to ionizing radiation orchemotherapy.

BACKGROUND OF THE DISCLOSURE

In humans, exposure to high doses of radiation can lead to thedevelopment of Acute Radiation Syndrome (ARS) often referred to asradiation sickness. Irradiation of the body has cytotoxic effects oncells and tissues as it damages essential molecular structures withinthe cells such as DNA, RNA, proteins, etc. Hematopoietic,gastrointestinal, and neurovascular cells are most vulnerable to theadverse effects of ionizing radiation. Depletion of these cells isresponsible for many of the observed symptoms of ARS.

Depending on the radiation dose and extent of exposure, ARS can manifestas bone marrow syndrome, gastrointestinal syndrome, and/or cutaneous andcardiovascular (CV)/central nervous system (CNS) syndrome. The syndromehas three distinct stages—the prodromal phase, the latent asymptomaticphase, and the overt systemic illness phase—each of which ischaracterized by the different symptoms of ARS that develop over time(Bushberg, Jerrold T. “Radiation Exposure and Contamination” MerckManual (2020)). In many cases, ARS is fatal due to irreparable damage tothe body's organs and tissues. In cases where the individual survives,however, recovery from ARS can take up to two years (Acute RadiationSyndrome: A Fact Sheet for Physicians. CDC (2005)).

Individuals, such as first-responders, nuclear power plant workers,pilots, flight attendants and astronauts can be exposed to high doses ofradiation in the occupation setting. Emergency personnel, such aspolicemen, firefighters, and military members, can likewise be exposedto radiation while responding to an attack or accident involvingradioactive material or during the decommissioning reactors. Individualswhose professions require space travel are also more likely to beexposed to harmful amounts of space radiation. In particular, spaceradiation exhibits increased ionization and is composed of manydifferent types of radiation, including that from solar flares, coronalmass ejections, galactic cosmic rays, and radioactive particles withinthe Earth's magnetic field. NASA estimates that crews on theInternational Space Station are subjected to radiation doses rangingfrom 80 mSv-160 mSv during a six-month mission (NASA Facts:Understanding Space Radiation. National Aeronautics and SpaceAdministration (2004)). Furthermore, the average radiation exposureexperienced by astronauts is increased during spacewalk excursionsoutside of the space station or vehicle. Longer, extended deep spaceflight (such as the 3-year mission to Mars projected to be completed bythe 2030s) would expose astronauts to even higher levels of radiation,levels which could effectively put an entire mission at risk (Redd, NolaTaylor “Radiation Remains a Problem for Any Mission to Mars,” May 17,2016, Smithsonian). Engineers have yet to develop effective methods toshield astronauts from increased radiation exposure and radiationscientists emphasize the need for research and development in the comingyears as an adjunct to prudent planning for a such a mission to Mars(Redd, Nola Taylor “Radiation Remains a Problem for Any Mission toMars,” May 17, 2016, Smithsonian).

Therapeutic radiation for the treatment of cancer and other conditionsis a more common source of radiation exposure among humans. For example,by applying radiation to proliferative cancer cells, this therapy aimsto eliminate or to reduce the size of malignant tumors in the body.Despite efforts to target the radiation to isolated areas of abnormaltissue, therapeutic radiation still exposes normal healthy tissue to thecytotoxic effects of ionizing radiation leading to side effects.Currently, amifostine (Ethyol®):

is the only FDA-approved radioprotector for individuals undergoingtherapeutic radiation treatment for cancer (Radiation Therapy forCancer. National Cancer Institute (2019)). This agent, however, is onlyapproved for protecting salivary glands from the damaging effects ofradiation, and must be administered intravenously. In addition, thisagent is associated with toxicities that can limit its use, such astransient hypotension and nausea and vomiting. Aside from the use ofleucovorin to protect against the toxicity of methotrexate, there is nooral, multi-organ radioprotector available for subjects undergoingchemotherapy and/or therapeutic radiation. There is, therefore, aglaring need for an oral chemo- and radio-protector that has ease ofadministration, reduced costs and likely reduced adverse reactions, withminimal loss of efficacy for the treated tumor, versus the currentlyavailable intravenous therapy.

There is also a need to develop an effective orally bioavailableradioprotective compound that is capable of providing systemicprotection from the harmful effects of ionizing radiation to the body'shealthy tissues. An easily-administered pharmaceutical composition wouldbe the most practical means of protection in both radiologicalemergencies and exposures and therapeutic radiation treatments.

Exposure to radiation can also lead to oxidative stress, i.e., animbalance between free radicals and antioxidants in the body. Oxidativestress results in damage to biomolecules such as lipids, proteins andDNA. This damage often leads to the development of chronic diseases suchas atherosclerosis, cancer, diabetes, rheumatoid arthritis,post-ischemic perfusion injury, myocardial infarction, cardiovasculardiseases, chronic inflammation, stroke, septic shock, aging and otherdegenerative diseases (Uttara, B., et al., Oxidative Stress andNeurodegenerative Diseases: A Review of Upstream and DownstreamAntioxidant Therapeutic Options, Current Neuropharmacology, 2009, 7,65-74). Oxidative stress is also considered a contributing factor inaging (Kregel, K. C., et al, “An integrated view of oxidative stress inaging: basic mechanisms, functional effects, and pathologicalconsiderations”, Am. J. Physiol. Regul. Integr. Comp. Physiol, 2007,292, R18-R36) and inflammatory disorders (Mittal, M., et al., “ReactiveOxygen Species in Inflammation and Tissue Injury”, Antioxidants & RedoxSignaling, 2014, 20(7), 1126-1167). Additionally, hereditary conditionsthat are associated with mutations in mitochondrially expressed geneshave been linked to oxidative stress, including Friedreich ataxia,Leber's hereditary optic neuropathy (LHON), myoclonus epilepsy, raggedred fiber disease (MERRF), mitochondrial encephalomyapathy, lacticacidosis and stroke-like episodes (MELAS) (Hayashi, G.; Cortopassi, G.,“Oxidative stress in inherited mitochondrial diseases”, Free RadicalBiology and Medicine, 2015, 88, 10-17). Thus, there is a need to developan effective reactive oxygen species (ROS) scavenger that is capable oftreating diseases, disorders or conditions associated with oxidativestress.

SUMMARY OF THE DISCLOSURE OF THE APPLICATION

In one aspect, the disclosure is directed to a compound having astructure according to formula I:

-   or a pharmaceutically acceptable salt, solvate, hydrate, or    polymorph thereof, or a solvate, hydrate, or polymorph of the    pharmaceutically acceptable salt, wherein;-   each R⁰ is independently hydrogen, (C1-C3)alkyl, or —SH;-   A is selected from hydrogen, Moiety A¹, Moiety A² or Moiety A³:

-   -   wherein each of R¹ and R² is independently selected from the        group consisting of hydrogen, —(CH(R⁶))—O—C(O)R¹⁰,        —(CH(R⁶))_(m)—S—C(O)R¹⁰ and —CH₂—(C(R¹¹)₂)—C(O)—CH₂—S—C(O)R¹⁰;        wherein m is an integer selected from the group consisting of 0,        1, 2, 3, and 4;or R¹ and R², one of which is CH₂ or the other is        CH₂CH₂, taken with the —O—P—O— linkage to which they are        attached, form a 6-membered heterocycloalkyl ring that is        independently substituted with 1-2 R^(a) and 0-3 R^(b);    -   wherein each R^(a) is independently hydrogen, (C1-C6)alkyl,        (C6-C10)aryl- or a 5- to 10-membered heteroaryl-, provided that        at least one R^(a) group is (C6-C10)aryl- or a 5- to 10-membered        heteroaryl-, wherein said alkyl, aryl and heteroaryl R^(a) is        substituted with 0-3 R^(c);    -   wherein, when present, each R^(b) is —(C1-C3)alkyl;    -   wherein each R^(c) is independently selected from the group        consisting of halogen, (C1-C3)alkyl, —CN, —O—(C1-C3)alkyl,        —S—(C1-C3)alkyl, —C(O)O—(C1-C3)alkyl, —N(R′)₂, —CF₃ and —OCF₃;    -   wherein each R⁶ is independently hydrogen or (C1-C3)alkyl;    -   wherein each R¹⁰ is selected from the group consisting of        —(C1-C6)alkyl, —O—(C1-C6)alkyl, —O—(C6-C10)aryl, —(C6-C10)aryl,        (5- to 10-membered)heteroaryl, (4- to        10-membered)heterocycloalkyl, (C3 -C10)cycloalkyl, —O-(5- to        10-membered)heteroaryl, —O-(4- to 10-membered)heterocycloalkyl,        —O—(C3-C10)cycloalkyl, —O-(4- to 20-membered)heteroalkyl, -(4-        to 20-membered)heteroalkyl, -[(CH₂)_(y)O]_(z)—R,        —CH₂—O—[(CH₂)_(y)O]_(z)—R and —O—[(CH₂)_(y)O]_(z)—R, wherein        each of said heteroalkyl, heterocycloalkyl, and heteroaryl        independently have 1-6 oxygen atoms, wherein y is an integer        between 1 and 4, wherein z is an integer between 1 and 10,        wherein R is hydrogen or (C1-C6)alkyl and wherein each R¹⁰ is        independently substituted with 0-3 R^(c);    -   wherein each R¹¹ is independently selected from the group        consisting of hydrogen, —(C1-C6)alkyl, —CH₂—O—C(O)R″, —C(O)—OR″,        -(4- to 20-membered)heteroalkyl, —O-(4- to        20-membered)heteroalkyl, —[(CH₂)_(y)O]_(z)—R,        —CH₂—O—[(CH₂)_(y)O]_(z)—R and —O—[(CH₂)_(y)O]_(z)—R, wherein        each of said heteroalkyls independently has 1-6 oxygen atoms,        wherein y is an integer between 1 and 4, wherein z is an integer        between 1 and 10, and wherein R is hydrogen or (C1-C6)alkyl;

-   -   wherein W and Y are independently selected from N or CH;    -   wherein R³ is hydrogen, halogen, (C1-C6)alkyl,        (C3-C7)cycloalkyl, (5- to 8-membered)heterocycloalkyl,        —O—(C1-C6)alkyl, —O—(C3-C7)cycloalkyl, —O—(5- to        8-membered)heterocycloalkyl, (C2-C6)alkenyl, —CH₂OH, phenyl, (5-        to 6-membered)heteroaryl, or (5- to 6-membered)heterocycloalkyl,        wherein R³ is substituted with 0-3 substituents selected from        the group consisting of halogen, oxo, —CN, —(C1-C6)alkyl,        —O—(C1-C6)alkyl, and —C(O)O(C1-C3)alkyl;    -   wherein R⁴ is hydrogen, —CN, (C1-C6)alkyl, —O—(C1-C6)alkyl,        (C2-C6)alkenyl or —CH₂OH;    -   or R⁴ and R³ are taken together with the carbon atoms to which        they are attached to form a (C5-C6)cycloalkyl, (C6-C10)aryl, (5-        to 10-membered)heterocycloalkyl or (5- to        10-membered)heteroaryl;    -   wherein R⁵ is hydrogen, halogen, (C1-C6)alkyl or        —O—(C1-C6)alkyl; or R⁵ and R⁴ are taken together with the carbon        atoms to which they are attached to form a (C5-C6)cycloalkyl,        phenyl, (5- or 6-membered)heterocycloalkyl, or (5- or        6-membered)heteroaryl; wherein R¹⁴ is —(C1-C6)alkyl;    -   wherein R¹⁵ is hydrogen, —(C1-C6)alkyl, —CH₂-phenyl, or        —CH₂-(5-to 10-membered)heteroaryl, wherein the —(C1-C6)alkyl,        —CH₂-phenyl, or —CH₂-(5-to 10-membered)heteroaryl are        substituted with 0-3 substituents selected from the group        consisting of —OH, —SH, —SCH₃, —C(O)NH₂, —C(O)OH, —NH₂ and        —NH—C(═NH)NH₂;    -   wherein R¹⁶ is hydrogen or —(C1-C6)alkyl;

-   -   wherein R⁷ is selected from the group consisting of        —(C1-C3)alkyl, —(C3-C6)cycloalkyl, and -(4- to        6-membered)heterocycloalkyl, wherein R⁷ is substituted with 0-3        R″;    -   wherein R⁸ and R⁹ are independently selected from the group        consisting of hydrogen, —(C1-C3)alkyl, —(C3-C6)cycloalkyl, and        -(4- to 6-membered)heterocycloalkyl, wherein R⁸ and R⁹ are        independently substituted with 0-3 R″;    -   wherein R″ is hydrogen, halogen, —(C1-C6)alkyl, —O—(C2-C6)alkyl,        -(4- to 20-membered)heteroalkyl, or —[(CH₂)_(y)O]_(z)—R, wherein        said heteroalkyl has 1-6 oxygen atoms, wherein y is an integer        between 1 and 4, wherein z is an integer between 1 and 10, and        wherein R is hydrogen or (C1-C6)alkyl;    -   wherein B is a (6- to 8-membered)heterocycloalkyl containing two        N atoms , wherein B is substituted with a (C1-C4)alkyl,        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, so as to form        a bicyclic ring, and/or substituted with 0-3 (C1-C4)alkyl,        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heteroaryl,        (C1-C6)aryl, (C5 to C6)heteroaryl, (C1-C4)acyl, (C1-C4)alkenyl        and (C1-C4)alkynyl, wherein the (C1-C4)alkyl, (C1-C4)alkenyl and        (C1-C4)alkynyl are optionally substituted with 1-3 halogen or        (C1-C4)alkoxy;

-   or is selected from Moiety B¹ or Moiety B², wherein Moiety B¹ has    the structure:

-   -   wherein each occurrence of R¹² and R¹³ is independently selected        from the group consisting of hydrogen, —(C1-C10)alkyl,        —(C3-C10)cycloalkyl, -(4- to 10-membered) heteroaryl, and -(4-        to 10-membered)heterocycloalkyl, wherein each of R¹² and R¹³ is        independently substituted with 0-3 R′; or    -   wherein two R¹³ groups taken with the nitrogen atoms to which        they are attached combine to form a (7- to        8-membered)heterocycloalkyl, wherein the (7- to        8-membered)heterocycloalkyl is substituted with 0-3        (C1-C4)alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,        so as to form a bicyclic ring, and/or substituted with 0-3        (C1-C4)alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,        heteroaryl, (C1-C6)aryl, (C5 to C6)heteroaryl, (C1-C4)acyl,        (C1-C4)alkenyl and (C1-C4)alkynyl, wherein the (C1-C4)alkyl,        (C1-C4)alkenyl and (C1-C4)alkynyl are optionally substituted        with 1-3 halogen or (C1-C4)alkoxy;    -   wherein R′ is selected from hydrogen, halogen, (C1-C4)alkyl, or        —O—(C1-C4)alkyl; and wherein Moiety B² has the structure:

-   -   wherein n is an integer selected from the group consisting of 1,        2, 3, and 4; and provided that the compound is not

In one embodiment, the disclosure is directed to a compound having astructure according to formula II,

or a pharmaceutically acceptable salt, solvate, hydrate, or polymorphthereof, or a solvate, hydrate, or polymorph of the pharmaceuticallyacceptable salt, wherein R⁰, R¹, R₂, R¹², and R¹³ are as defined informula I.

In another embodiment, the disclosure is directed to a compound having astructure according to formula III,

-   or a pharmaceutically acceptable salt, solvate, hydrate, or    polymorph thereof, or a solvate, hydrate, or polymorph of the    pharmaceutically acceptable salt, wherein R⁰, R¹², and R¹³ are as    defined in formula I, and wherein:-   R^(a1) and R^(a2) are independently selected from hydrogen,    (C1-C6)alkyl, (C6-C10)aryl or a 5- to 10-membered heteroaryl,    wherein said alkyl, aryl and heteroaryl are substituted with 0-3    R^(c), provided that at least one of R^(a1) and R^(a2) is    (C6-C10)aryl or a 5- to 10-membered heteroaryl;-   R^(d) is hydrogen or (C1-C3)alkyl; and-   R^(e1) and R^(e2) are independently hydrogen or (C1-C3)alkyl,    provided that when R^(a1) is (C6-C10)aryl or a 5- to 10-membered    heteroaryl, R^(e1) is hydrogen, and that when R^(a2) is (C6-C10)aryl    or a 5- to 10-membered heteroaryl, R^(e2) is hydrogen.

In another embodiment, the disclosure is directed to a compound having astructure according to formula IV,

-   or a pharmaceutically acceptable salt, solvate, hydrate, or    polymorph thereof, or a solvate, hydrate, or polymorph of the    pharmaceutically acceptable salt, wherein Y, W, R⁰, R⁴, R⁵, R¹²,    R¹³, R¹⁴, R¹⁵, and R¹⁶ are as defined in formula I, and wherein:-   R³ is (C1-C6)alkyl, (C3-C7)cycloalkyl, (5- to    8-membered)heterocycloalkyl, —O—(C1-C6)alkyl, —O—(C3-C7)cycloalkyl,    —O-(5- to 8-membered)heterocycloalkyl, (C2-C6)alkenyl, —CH₂OH,    phenyl, (5- or 6-membered)heteroaryl, or (5- or    6-membered)heterocycloalkyl, wherein R³ is substituted with 0-3    substituents selected from the group consisting of halogen, oxo,    —(C1-05)alkyl, —O—(C2-C4)alkyl, and —C(O)O(C1-C3)alkyl.

In one embodiment, the disclosure is directed to a compound having astructure according to formula V,

-   or a pharmaceutically acceptable salt, solvate, hydrate, or    polymorph thereof, or a solvate, hydrate, or polymorph of the    pharmaceutically acceptable salt, wherein R⁰, R⁷, R⁸, R⁹, R¹², and    R¹³ are as defined in formula I, and wherein:-   R″ is halogen, —(C1-C6)alkyl or —O—(C2-C6)alkyl.

In another embodiment, the disclosure is directed to a compound having astructure according to formula VI:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,prodrug or double prodrug thereof, or a solvate, hydrate, or polymorphof the pharmaceutically acceptable salt, wherein R⁰, R¹², and R¹³ are asdefined in formula I, provided that the compound is not

In another embodiment, the disclosure is directed to a compound having astructure according to formula VII:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,prodrug or double prodrug thereof, or a solvate, hydrate, or polymorphof the pharmaceutically acceptable salt, wherein R⁰ and B are as definedin formula I, provided that the compound is not

In one aspect, this disclosure is directed to a method of treating orpreventing a toxicity or condition associated with ionizing radiationexposure in a subject in need of said radiation, comprisingadministering to the subject a therapeutically effective or protectiveamount of a compound of this disclosure, or of a pharmaceuticalcomposition thereof.

In another aspect, this disclosure is directed to a method of protectingnormal tissues in a subject against toxicities associated with radiationtherapy with minimal adverse effects on the tumor response to thosetreatments, the method comprising administering to said subject atherapeutically effective amount of a compound or pharmaceuticalcomposition of this disclosure.

In one aspect, this disclosure is directed to a method of protectingnormal tissues in a subject against toxicities associated withchemotherapy with minimal adverse effects on the tumor response to thosetreatments, the method comprising administering to said subject atherapeutically effective amount of a compound or pharmaceuticalcomposition this disclosure.

In another aspect, this disclosure is directed to a method of reducingthe risk of secondary tumor induction in a subject being treated withradiation therapy, the method comprising administering to said subject atherapeutically effective amount of a compound or pharmaceuticalcomposition of this disclosure.

In one aspect, this disclosure is directed to a method of reducing therisk of secondary tumor induction in a subject being treated withchemotherapy, the method comprising administering to said subject atherapeutically effective amount of a compound or pharmaceuticalcomposition of this disclosure.

In another aspect, this disclosure is directed to a method of reducingthe risk of tumor induction in a subject who has been exposed to, isbeing exposed to, or will be exposed to ionizing radiation, the methodcomprising administering to said subject a protective amount of acompound or pharmaceutical composition of this disclosure.

In another aspect, this disclosure is directed to a method of slowingthe aging process in a subject, wherein the method comprisesadministering a compound or pharmaceutical composition of thisdisclosure.

In another aspect, this disclosure is directed to a method of treating adisease or condition in a subject in need thereof comprisingadministering a compound or a pharmaceutical composition of thisdisclosure.

In one aspect, this disclosure is directed to a pharmaceuticalcomposition or a crystalline salt form of one of the aspects of thisdisclosure and a pharmaceutically acceptable carrier.

In one embodiment, the pharmaceutical composition of this disclosurefurther comprises an antioxidant.

In one embodiment, a pharmaceutical composition of this disclosure isco-administered (concurrently, separately or sequentially) with anantioxidant as described herein. In another embodiment, the antioxidantis selected from the group consisting of ascorbic acid, ascorbate,vitamin C, N-acetylcysteine, glutathione, lipoic acid, uric acid,alphα-tocopherol, vitamin E, beta-carotene, vitamin A, retinol, andubiquinol.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a Kaplan-Meier plot with survival curves of mice treatedwith vehicle, PrC-210, DzCH2SH or 2Pip-PrSH prior to total bodyirradiation with 9.9 Gy.

DETAILED DESCRIPTION OF THE DISCLOSURE Exemplary Embodiments

Exemplary embodiments of the disclosure include:

-   1. A compound having a structure according to formula I:

-   or a pharmaceutically acceptable salt, solvate, hydrate, or    polymorph thereof, or a solvate, hydrate, or polymorph of the    pharmaceutically acceptable salt, wherein;-   each R⁰ is independently hydrogen, (C1-C3)alkyl, or —SH;-   A is selected from hydrogen, Moiety A¹, Moiety A² or Moiety A³:

-   -   wherein each of R¹ and R² is independently selected from the        group consisting of hydrogen, —(CH(R⁶))—O—C(O)R¹⁰,        —(CH(R⁶))_(m)—S—C(O)R¹⁰ and —CH₂—(C(R¹¹)₂)—C(O)—CH₂—S—C(O)R¹⁰;    -   wherein m is an integer selected from the group consisting of 0,        1, 2, 3, and 4; or R¹ and R², one of which is CH₂ or the other        of which is CH₂CH₂, taken with the —O—P—O— linkage to which they        are attached form a 6-membered heterocycloalkyl ring that is        independently substituted with 1-2 R^(a) and 0-3 R^(b);    -   wherein each R^(a) is independently hydrogen, (C1-C6)alkyl,        (C6-C10)aryl- or a 5- to 10-membered heteroaryl-, wherein said        alkyl, aryl and heteroaryl is substituted with 0-3 R^(c),        provided that at least one R^(a) group is (C6-C10)aryl- or a 5-        to 10-membered heteroaryl-;    -   wherein when present, each R^(b) is —(C1-C3)alkyl;    -   wherein when present each R^(c) is independently selected from        the group consisting of halogen, (C1-C3)alkyl, —CN,        —O—(C1-C3)alkyl, —S—(C1-C3)alkyl, —C(O)O—(C1-C3)alkyl, —N(R′)₂,        —CF₃ and —OCF₃;    -   wherein each R⁶ is independently hydrogen or        (C1-C3)alkyl;wherein each R¹⁰ is selected from the group        consisting of —(C1-C6)alkyl, —O—(C1-C6)alkyl, —O—(C6-C10)aryl,        —(C6-C10)aryl, (5- to 10-membered)heteroaryl, (4- to        10-membered)heterocycloalkyl, (C3-C10)cycloalkyl, —O—(5- to        10-membered)heteroaryl, —O—(4- to 10-membered)heterocycloalkyl,        —O—(C3-C10)cycloalkyl, —O—(4- to 20-membered)heteroalkyl, -(4-        to 20-membered)heteroalkyl, —[(CH₂)_(y)O]_(z)—R,        —CH₂—O—[(CH₂)_(y)O]_(z)—R and —O—[(CH₂)_(y)O]_(z)—R, wherein        each of said heteroalkyl, heterocycloalkyl and heteroaryl        independently have 1-6 oxygen atoms, wherein y is an integer        between 1 and 4, wherein z is an integer between 1 and 10,        wherein R is hydrogen or (C1-C6)alkyl, and wherein each R¹⁰ is        independently substituted with 0-3 R^(c);    -   each R¹¹ is independently selected from the group consisting of        hydrogen, —(C1-C6)alkyl, —CH₂—O—C(O)R″, —C(O)—OR″, -(4- to        20-membered)heteroalkyl, —O—(4- to 20-membered)heteroalkyl,        —[(CH₂)_(y)O]_(z)—R, —CH₂—O—[(CH₂)_(y)O]_(z)—R and        —O—[(CH₂)_(y)O]_(z)—R, wherein each of said heteroalkyl        independently has 1-6 oxygen atoms, wherein y is an integer        between 1 and 4, wherein z is an integer between 1 and 10, and        wherein R is hydrogen or (C1-C6)alkyl;

-   -   wherein W and Y are independently selected from N or CH;    -   wherein R³ is hydrogen, halogen, (C1-C6)alkyl,        (C3-C7)cycloalkyl, (5- to 8-membered)heterocycloalkyl,        —O—(C1-C6)alkyl, —O—(C3-C7)cycloalkyl, —O—(5- to        8-membered)heterocycloalkyl, (C2-C6)alkenyl, —CH₂OH, phenyl, (5-        to 6-membered)heteroaryl, or (5- to 6-membered)heterocycloalkyl,        wherein R³ is substituted with 0-3 substituents selected from        the group consisting of halogen, oxo, cyano, —(C1-C6)alkyl,        —O—(C1-C6)alkyl, and —C(O)O(C1-C3)alkyl;    -   wherein R⁴ is hydrogen, —CN, (C1-C6)alkyl, —O—(C1-C6)alkyl,        —(C2-C6)alkenyl or —CH₂OH; or R⁴ and R³ are taken together with        the carbon atoms to which they are attached to form a        (C5-C6)cycloalkyl, (C6-C10)aryl, (5- to        10-membered)heterocycloalkyl or (5- to 10-membered)heteroaryl;    -   wherein R⁵ is hydrogen, halogen, (C1-C6)alkyl or        —O—(C1-C6)alkyl; or R⁵ and R⁴ are taken together with the carbon        atoms to which they are attached to form a (C5-C6)cycloalkyl,        phenyl, (5- or 6-membered)heterocycloalkyl, or (5- or        6-membered)heteroaryl;    -   wherein R¹⁴ is —(C1-C6)alkyl;    -   wherein R¹⁵ is hydrogen, —(C1-C6)alkyl, —CH₂-phenyl, or        —CH₂-(5-to 10-membered)heteroaryl, wherein the —(C1-C6)alkyl,        —CH₂-phenyl, or —CH₂-(5-to 10-membered)heteroaryl are        substituted with 0-3 substituents selected from the group        consisting of —OH, —SH, —SCH₃, —C(O)NH₂, —C(O)OH, —NH₂ and        —NH—C(═NH)NH₂;    -   R¹⁶ is hydrogen or —(C1-C6)alkyl;

-   -   wherein R⁷ is selected from the group consisting of        —(C1-C3)alkyl, —(C3-C6)cycloalkyl, and -(4- to        6-membered)heterocycloalkyl, wherein R⁷ is substituted with 0-3        R″;    -   wherein R⁸ and R⁹ are independently selected from the group        consisting of hydrogen, —(C1-C3)alkyl, —(C3-C6)cycloalkyl, and        -(4- to 6-membered)heterocycloalkyl, wherein R⁸ and R⁹ are        independently substituted with 0-3 R″;    -   wherein R″ is hydrogen, halogen, —(C1-C6)alkyl, —O—(C2-C6)alkyl,        or -(4- to 20-membered)heteroalkyl, wherein said heteroalkyl has        1-6 oxygen atoms;    -   wherein B is a (6- to 8-membered)heterocycloalkyl containing two        N atoms, Moiety B¹, or Moiety B², wherein B is substituted with        a (C1-C4)alkyl, cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl, so as to form a bicyclic ring, and/or substituted        with 0-3 (C1-C4)alkyl, cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl, heteroaryl, (C1-C6)aryl, (C5 to C6)heteroaryl,        (C1-C4)acyl, (C1-C4)alkenyl and (C1-C4)alkynyl, wherein the        (C1-C4)alkyl, (C1-C4)alkenyl and (C1-C4)alkynyl are optionally        substituted with 1-3 halogen or (C1-C4)alkoxy;    -   wherein Moiety B¹ has the structure:

-   -   wherein each occurrence of R¹² and R¹³ is independently selected        from the group consisting of hydrogen, —(C1-C10)alkyl,        —(C3-C10)cycloalkyl, -(4- to 10-membered)heteroaryl, and -(4- to        10-membered)heterocycloalkyl, wherein each of R¹² and R¹³ is        independently substituted with 0-3 R′; or    -   wherein two R¹³ groups taken with the nitrogen atoms to which        they are attached combine to form a (7- to        8-membered)heterocycloalkyl, wherein the (7- to        8-membered)heterocycloalkyl is substituted with a (C1-C4)alkyl,        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, so as to form        a bicyclic ring, and/or substituted with 0-3 (C1-C4)alkyl,        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heteroaryl,        (C1-C6)aryl, (C5 to C6)heteroaryl, (C1-C4)acyl, (C1-C4)alkenyl        and (C1-C4)alkynyl, wherein the (C1-C4)alkyl, (C1-C4)alkenyl and        (C1-C4)alkynyl are optionally substituted with 1-3 halogen or        (C1-C4)alkoxy;    -   wherein R′ is selected from hydrogen, halogen, (C1-C4)alkyl, or        —O—(C1-C4)alkyl; and    -   wherein Moiety B² has the structure:

-   -   wherein n is an integer selected from the group consisting of 1,        2, 3, and 4; and    -   provided that the compound is not

-   2. The compound according to embodiment 1, or a pharmaceutically    acceptable salt, solvate, hydrate, or polymorph thereof, or a    solvate, hydrate, or polymorph of the pharmaceutically acceptable    salt, wherein B is a heterocycle selected from the group consisting    of

-   -   wherein B is optionally substituted with a (C1-C4)alkyl,        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, so as to form        a bicyclic ring, and/or substituted with 0-3 (C1-C4)alkyl,        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heteroaryl, (C        1-C6)aryl, (C5 to C6)heteroaryl, (C1-C4)acyl, (C1-C4)alkenyl and        (C1-C4)alkynyl, wherein the (C1-C4)alkyl, (C1-C4)alkenyl and        (C1-C4)alkynyl are optionally substituted with 1-3 halogen or        (C1-C4)alkoxy.

-   3. The compound according to embodiment 1, or a pharmaceutically    acceptable salt, solvate, hydrate, or polymorph thereof, or a    solvate, hydrate, or polymorph of the pharmaceutically acceptable    salt, wherein the compound has a structure according to formula II:

or a pharmaceutically acceptable salt, solvate, hydrate, or polymorphthereof, or a solvate, hydrate, or polymorph of the pharmaceuticallyacceptable salt.

-   4. The compound according to embodiment 3, or a pharmaceutically    acceptable salt, solvate, hydrate, or polymorph thereof, or a    solvate, hydrate, or polymorph of the pharmaceutically acceptable    salt, wherein:-   each R⁰ is hydrogen;-   wherein each of R¹ and R² is independently hydrogen or    —(CH(R⁶))—O—C(O)R¹⁰;-   wherein each R⁶ is independently hydrogen or (C1-C3)alkyl; and-   wherein each R¹⁰ is independently selected from the group consisting    of —(C1-C6)alkyl, —O—(C1-C6)alkyl, —(C6-C10)aryl, -(4- to    20-membered)heteroalkyl, —O-(4- to 20-membered)heteroalkyl,    —[(CH₂)_(y)O]_(z)—R, —CH₂—O—[(CH₂)_(y)O]_(z)—R and    —O—[(CH₂)_(y)O]_(z)—R, wherein each of said heteroalkyl    independently has 1-6 oxygen atoms, wherein y is an integer between    1 and 4, wherein z is an integer between 1 and 10, wherein R is    hydrogen or (C1-C6)alkyl, and wherein each R¹⁰ is independently    substituted with 0-3 R_(c) groups;-   wherein R^(c) is selected from the group consisting of halogen,    (C1-C3)alkyl, —CN, —O—(C1-C3)alkyl, —S—(C1-C3)alkyl, and    —O—C(O)(C1-C3)alkyl;-   wherein each R¹² is hydrogen; and-   wherein each R¹³ is (C1-C3)alkyl.-   5. The compound according to embodiment 3, or a pharmaceutically    acceptable salt, solvate, hydrate, or polymorph thereof, or a    solvate, hydrate, or polymorph of the pharmaceutically acceptable    salt, wherein:-   each R⁰ is hydrogen;-   wherein each of R¹ and R² is independently hydrogen,    —(CH(R⁶))_(m)—S—C(O)R¹⁰ or —CH₂—(C(R¹¹)₂)—C(O)—CH₂—S—C(O)R¹⁰;-   wherein each R¹² is hydrogen;-   wherein each R¹³ is a (C1-C3)alkyl;-   wherein each R⁶ is hydrogen;-   wherein R¹⁰ is selected from the group consisting of (C1-C6)alkyl,    and (C6-C10)aryl, wherein each R¹⁰ is substituted with 0-3 R^(c);-   each R¹¹ is independently selected from the group consisting of    hydrogen, —(C1-C6)alkyl, —CH₂—O—C(O)R″ and —C(O)—OR″;-   each R^(c) is (C1-C3)alkyl or —C(O)O—(C1-C3)alkyl;-   R″ is hydrogen, (C1-C6)alkyl, or -(4- to 20-membered)heteroalkyl,    wherein said heteroalkyl has 1-6 oxygen atoms; and-   m is an integer selected from the group consisting of 0, 1, 2, 3 and    4.

6. The compound according to embodiment 1, wherein the compound has astructure according to formula III:

-   or a pharmaceutically acceptable salt, solvate, hydrate, or    polymorph thereof, or a solvate, hydrate, or polymorph of the    pharmaceutically acceptable salt, wherein:-   R^(a1) and R^(a2) are independently selected from hydrogen,    (C1-C6)alkyl, (C6-C10)aryl or a 5- to 10-membered heteroaryl,    wherein said alkyl, aryl and heteroaryl are substituted with 0-3    R^(c), provided that at least one of R^(a1) and R^(a2) is    (C6-C10)aryl or a 5- to 10-membered heteroaryl;-   wherein each R^(c) is independently selected from the group    consisting of halogen, (C1-C3)alkyl, —CN, —O—(C1-C3)alkyl,    —S—(C1-C3)alkyl, —C(O)O—(C1-C3)alkyl, —N(R′)₂, —

CF3 and -OCF3;

-   wherein R^(d) is hydrogen or (C1-C3)alkyl; and-   wherein R^(e1) and R^(e2) are independently hydrogen or    (C1-C3)alkyl, provided that when R^(a1) is (C6-C10)aryl or a 5- to    10-membered heteroaryl, R^(e1) is hydrogen, and that when R^(a2) is    (C6-C10)aryl or a 5- to 10-membered heteroaryl, R^(e2) is hydrogen.-   7. The compound according to embodiment 6, or a pharmaceutically    acceptable salt, solvate, hydrate, or polymorph thereof, or a    solvate, hydrate, or polymorph of the pharmaceutically acceptable    salt wherein:-   each R⁰ is independently hydrogen;-   wherein each R¹² and R¹³ is independently selected from the group    consisting of hydrogen, —(C1-C3)alkyl, —(C3-C10)cycloalkyl, -(4- to    10-membered)heteroaryl, and -(4- to 10-membered)heterocycloalkyl,    wherein each of R¹² and R¹³ is independently substituted with 0-3    R′;-   wherein R^(a1) and R^(a2) is independently hydrogen, (C1-C6)alkyl,    (C6-C10)aryl or a 5- to 10-membered heteroaryl, wherein said alkyl,    aryl and heteroaryl are substituted with 0-3 R_(c), provided that at    least one of R^(a1) and R^(a2) is (C6-C10)aryl or a 5- to    10-membered heteroaryl;-   wherein R^(c) is selected from the group consisting of hydrogen,    halogen, (C1-C3)alkyl, —CN, —O—(C1-C3)alkyl, —S—(C1-C3)alkyl,    —C(O)O—(C1-C3)alkyl, —N(R′)₂, —CF₃ and —OCF₃;-   wherein R^(d) is hydrogen or (C1-C3)alkyl;-   wherein R^(e1) and R^(e2) are independently hydrogen or    (C1-C3)alkyl, provided that when R^(a1) is (C6-C10)aryl or a 5- to    10-membered heteroaryl, R^(e1) is hydrogen, and that when R^(a2) is    (C6-C10)aryl or a 5- to 10-membered heteroaryl, R^(e2) is hydrogen;    and-   wherein R′ is hydrogen or —(C1-C4)alkyl.-   8. The compound according to embodiment 7, or a pharmaceutically    acceptable salt, solvate, hydrate, or polymorph thereof, or a    solvate, hydrate, or polymorph of the pharmaceutically acceptable    salt, wherein:-   each R⁰ is hydrogen;-   wherein each R¹² is hydrogen;-   wherein each R¹³ is (C1-C3)alkyl;-   wherein one of R^(a1) and R^(a2) is (C6-C10)aryl or a 5- to    10-membered heteroaryl, and the other is hydrogen, wherein said aryl    or heteroaryl is substituted with 1-3 R^(c);-   wherein each R^(c) is halogen or (C1-C3)alkyl; and-   wherein each of R^(d), R^(e1) and R^(e2) is hydrogen.-   9. The compound according to embodiment 1, wherein the compound has    a structure according to formula IV:

or a pharmaceutically acceptable salt, solvate, hydrate, or polymorphthereof, or a solvate, hydrate, or polymorph of the pharmaceuticallyacceptable salt, wherein:

-   R³ is substituted with 0-3 substituents selected from the group    consisting of halogen, oxo, —(C1-C5)alkyl, —O—(C2-C4)alkyl, and    —C(O)O(C1-C3)alkyl;-   10. The compound according to embodiment 9, or a pharmaceutically    acceptable salt, solvate, hydrate, or polymorph thereof, or a    solvate, hydrate, or polymorph of the pharmaceutically acceptable    salt, wherein:-   each R⁰ is independently hydrogen or (C1-C3)alkyl;-   wherein each R¹² and R¹³ is independently selected from the group    consisting of hydrogen, —(C1-C4)alkyl, —(C3-C10)cycloalkyl, -(4- to    10-membered)heteroaryl, and -(4- to 6-membered)heterocycloalkyl,    wherein each R¹² and R¹³ is independently substituted with 0-3 R′;-   wherein R³ is hydrogen, halogen, (C1-C6)alkyl, (C3-C7)cycloalkyl,    (5- to 8-membered)heterocycloalkyl, —O—(C1-C6)alkyl,    —O—(C3-C7)cycloalkyl, —O-(5- to 8-membered)heterocycloalkyl,    (C2-C6)alkenyl, —CH₂OH, phenyl, (5- or 6-membered)heteroaryl, or (5-    or 6-membered)heterocycloalkyl, wherein R³ is substituted with 0-3    substituents selected from the group consisting of halogen, oxo,    —(C1-05)alkyl, —O—(C2-C4)alkyl, and —C(O)O(C1-C3)alkyl;-   R⁴ is hydrogen, —CN, (C1-C6)alkyl, —O—(C1-C6)alkyl, (C2-C6)alkenyl    or —CH₂OH; or-   R⁴ and R³ are taken together with the carbon atoms to which they are    attached to form a (C5-C6)cycloalkyl, (C6-C10)aryl, (5- to    10-membered)heterocycloalkyl or (5- to 10-membered)heteroaryl;-   R⁵ is hydrogen, halogen, (C1-C6)alkyl or —O—(C1-C6)alkyl; or-   R⁵ and R⁴ are taken together with the carbon atoms to which they are    attached to form a (C5-C6)cycloalkyl, phenyl, (5- or    6-membered)heterocycloalkyl, or (5- or 6-membered)heteroaryl;-   R¹⁴ is (C1-C6)alkyl;-   R¹⁵ is hydrogen, —(C1-C6)alkyl, —CH₂-phenyl, or —CH₂-(5-to    10-membered)heteroaryl, wherein the —(C1-C6)alkyl, —CH2-phenyl, or    —CH2-(5-to 10-membered)heteroaryl are substituted with 0-3    substituents selected from the group consisting of —OH, —SH, —SCH₃,    —C(O)NH₂, —C(O)OH, —NH₂ and —NH—C(═NH)NH₂;-   R¹⁶ is hydrogen or —(C1-C6)alkyl; and-   R′ is selected from hydrogen, halogen, (C1-C4)alkyl, or    —O—(C1-C4)alkyl.-   11. The compound according to embodiment 10, or a pharmaceutically    acceptable salt, solvate, hydrate, or polymorph thereof, or a    solvate, hydrate, or polymorph of the pharmaceutically acceptable    salt, wherein:-   each R⁰ is hydrogen;-   each R¹² is H;-   each R¹³ is independently hydrogen or —(C1-C10)alkyl;-   R³, R⁴ and R⁵ are H;-   R14 is (C1-C3)alkyl;-   R¹⁵ is (C1-C3)alkyl; and-   R¹⁶ is H.-   12. The compound according to embodiment 1, wherein the compound has    a structure according to formula V:

-   or a pharmaceutically acceptable salt, solvate, hydrate, or    polymorph thereof, or a solvate, hydrate, or polymorph of the    pharmaceutically acceptable salt, wherein:    -   R′ is halogen, —(C1-C4)alkyl, or —O—(C1-C4)alkyl; and    -   R″ is halogen, —(C1-C6)alkyl or —O—(C2-C6)alkyl.-   13. The compound according to embodiment 12, or a pharmaceutically    acceptable salt, solvate, hydrate, or polymorph thereof, or a    solvate, hydrate, or polymorph of the pharmaceutically acceptable    salt, wherein:-   each R⁰ is independently hydrogen or (C1-C3)alkyl;-   wherein each R¹² and R¹³ is independently selected from the group    consisting of hydrogen, —(C1-C3)alkyl, —(C3-C10)cycloalkyl, -(4- to    10-membered)heteroaryl, and -(4- to 10-membered)heterocycloalkyl,    wherein each R¹² and R¹³ is independently substituted with 0-3 R′;-   wherein R⁷ is selected from the group consisting of —(C1-C3)alkyl,    —(C3-C6)cycloalkyl, and -(4- to 6-membered)heterocycloalkyl, wherein    R⁷ is substituted with 0-3 R″;-   wherein R⁸ and R⁹ are independently selected from the group    consisting of hydrogen, —(C1-C3)alkyl, —(C3-C6)cycloalkyl, and -(4-    to 6-membered)heterocycloalkyl, wherein R⁸ and R⁹ are independently    substituted with 0-3 R″;-   wherein R′ is halogen, (C1-C4)alkyl, or —O—(C1-C4)alkyl; and-   wherein R″ is halogen, —(C1-C3)alkyl or —O—(C1-C3)alkyl.-   14. The compound according to embodiment 13, or a pharmaceutically    acceptable salt, solvate, hydrate, or polymorph thereof, or a    solvate, hydrate, or polymorph of the pharmaceutically acceptable    salt, wherein:-   each R⁰ is hydrogen;-   each R¹² is H;-   each R¹³ is independently —(C1-C3)alkyl; and-   R⁷, R⁸ and R⁹ are —(C1-C3)alkyl.-   15. The compound according to embodiment 1, wherein the compound has    a structure according to formula VI:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,prodrug or double prodrug thereof, or a solvate, hydrate, or polymorphof the pharmaceutically acceptable salt, provided that the compound isnot

-   16. The compound according to embodiment 15, or a pharmaceutically    acceptable salt, solvate, hydrate, or polymorph thereof, or a    solvate, hydrate, or polymorph of the pharmaceutically acceptable    salt, wherein:    -   each R⁰ is independently hydrogen, (C1-C3)alkyl, or —SH;    -   each R¹² is independently hydrogen, (C1-C3)alkyl or -(4- to        10-membered)heteroaryl;    -   each R¹³ is taken together with the nitrogen atoms to which they        are attached to form a (7- to 8-membered)heterocycloalkyl.-   17. The compound according to embodiment 1, wherein the compound has    a structure according to formula VII:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,prodrug or double prodrug thereof, or a solvate, hydrate, or polymorphof the pharmaceutically acceptable salt, provided that the compound isnot

-   18. The compound according to embodiment 17, or a pharmaceutically    acceptable salt, solvate, hydrate, or polymorph thereof, or a    solvate, hydrate, or polymorph of the pharmaceutically acceptable    salt, wherein:    -   each R⁰ is independently hydrogen, (C1-C3)alkyl, or —SH;    -   wherein B is a (6- to 8-membered)heterocycloalkyl containing two        N atoms, wherein B is substituted with a (C1-C4)alkyl,        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, so as to form        a bicyclic ring, and/or substituted with 0-3 (C1-C4)alkyl,        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, (C1-C6)aryl,        (C5 to C6)heteroaryl, (C1-C4)acyl, (C1-C4)alkenyl and        (C1-C4)alkynyl, wherein the (C1-C4)alkyl, (C1-C4)alkenyl and        (C1-C4)alkynyl are optionally substituted with 1-3 halogen or        (C1-C4)alkoxy    -   or B is Moiety B¹;    -   wherein when present, each occurrence of R¹² and R¹³ is        independently hydrogen, —(C1-C6)alkyl, or -(4- to        10-membered)heteroaryl.-   19. The compound according to embodiment 18, or a pharmaceutically    acceptable salt, solvate, hydrate, or polymorph thereof, or a    solvate, hydrate, or polymorph of the pharmaceutically acceptable    salt, wherein B is the heterocycle

wherein the heterocycle is substituted with a (C1-C4)alkyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, so as to form a bicyclic ring,and/or substituted with 0-3 (C1-C4)alkyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, (C1-C6)aryl, (C5 to C6)heteroaryl, (C1-C4)acyl,(C1-C4)alkenyl and (C1-C4)alkynyl, wherein the (C1-C4)alkyl,(C1-C4)alkenyl and (C1-C4)alkynyl are optionally substituted with 1-3halogen or (C1-C4)alkoxy.

-   20. The compound according to embodiment 1, wherein the compound is    selected from the group consisting of:

Compound Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

18-(S,S)

18-(R,S)

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

or a pharmaceutically acceptable salt, solvate, hydrate, or polymorphthereof, or a solvate, hydrate, or polymorph of the pharmaceuticallyacceptable salt.

-   21. A crystalline salt form of a compound according to any one of    embodiments 1-20, or a pharmaceutically acceptable salt, solvate,    hydrate, or polymorph thereof or a solvate, hydrate, or polymorph of    the pharmaceutically acceptable salt.-   22. The crystalline salt form according to embodiment 21, wherein    the salt is selected from the group consisting of chloride,    benzenesulfonate, 4-toluenesulfonate, cyclohexylsulfamate, fumarate,    bromide, maleate, malonate, oxalate, succinate, trifluoroacetate,    sulfamate, acetate, ascorbate, mucate, sulfate and    1,5-naphthalenedisulfonate.-   23. The crystalline salt form according to any one of embodiments    21-22, wherein the salt form is stable when stored at ambient    temperature for at least 1 year.-   24. A pharmaceutical composition comprising a compound according to    any one of embodiments 1-20, or the crystalline salt form according    to any one of embodiments 21-23 and a pharmaceutically acceptable    carrier.-   25. The pharmaceutical composition according to embodiment 24,    wherein the composition further comprises an antioxidant.-   26. The pharmaceutical composition according to embodiment 24,    wherein the composition is co-administered sequentially,    concurrently or separately, with an antioxidant.-   27. The pharmaceutical composition according to embodiment 24,    wherein the Compound is Compound 42 or Compound 50, and the    composition further comprises an antioxidant.-   28. The pharmaceutical composition according to any one of    embodiments 25-27, wherein the antioxidant is selected from the    group consisting of ascorbic acid, ascorbate, vitamin C,    N-acetylcysteine, glutathione, lipoic acid, uric acid, α-tocopherol,    β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol,    β-tocotrienol, γ-tocotrienol, δ-tocotrienol, vitamin E, carotene,    beta-carotene, vitamin A, retinol, selenocysteine,    cyanidine-3-glucoside, and ubiquinol.-   29. The pharmaceutical composition according to any one of    embodiments 25-27, wherein the antioxidant is a non-thiol    antioxidant.-   30. The pharmaceutical composition according to embodiment 29,    wherein the non-thiol antioxidant is selected from the group    comprising α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol,    α-tocotrienol, β-tocotrienol, γ-tocotrienol, δ-tocotrienol, vitamin    E, carotene, beta-carotene, ascorbate, vitamin C,    cyanidine-3-glucoside, selenocysteine, or combinations thereof.-   31. The pharmaceutical composition according to embodiment 29,    wherein the non-thiol antioxidant is selected from the group    consisting of α-tocopherol, β-tocopherol, γ-tocopherol,    δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol,    δ-tocotrienol, vitamin E, carotene, beta-carotene, ascorbate,    vitamin C, cyanidine-3-glucoside, selenocysteine, and combinations    thereof.-   32. The pharmaceutical composition according to embodiment 31,    wherein the non-thiol antioxidant is selected from the group    consisting of α-tocopherol, γ-tocotrienol, and selenocysteine.-   33. The pharmaceutical composition according to any one of    embodiments 25-32, wherein the pharmaceutical composition exhibits a    synergistic radioprotective effect in mammals, mammalian tissues    and/or cultured mammalian cells.-   34. The pharmaceutical composition according to any one of    embodiments 24-33, wherein the composition is suitable for oral,    transmucosal, transdermal, parenteral, topical or cutaneous    administration.-   35. The pharmaceutical composition according to embodiment 34,    wherein the composition is suitable for parenteral administration,    and the administration is subcutaneous, intravenous, intramuscular,    or intrathecal administration.-   36. The pharmaceutical composition according to embodiment 34,    wherein the composition is suitable for oral administration.-   37. The pharmaceutical composition according to any one of    embodiments 24-36, wherein the composition is stable at ambient    temperature for at least 1 year.-   38. A method of treating or preventing a toxicity or condition    associated with ionizing radiation exposure in a subject in need    thereof, comprising administering to said subject a therapeutically    effective amount of a compound according to any one of embodiments    1-20, or a pharmaceutically acceptable salt, solvate, hydrate, or    polymorph thereof or a solvate, hydrate, or polymorph of the    pharmaceutically acceptable salt, or of a pharmaceutical composition    according to any one of embodiments 24-37.-   39. The method according to embodiment 38, wherein the source of the    ionizing radiation is nuclear warfare, a nuclear reactor, air    travel, or space travel.-   40. The method according to embodiment 39, wherein the source of the    ionizing radiation is space travel, and the radiation is from one or    more of galactic cosmic rays, chronic solar radiation, solar flares    or coronal mass ejections.-   41. The method according to embodiment 38, wherein the source of    ionizing radiation is radiation therapy.-   42. The method of any one of embodiments 38-41, wherein the ionizing    radiation exposure is acute radiation exposure.-   43. The method of any one of embodiments 38-41, wherein the ionizing    radiation exposure is chronic radiation exposure.-   44. The method according to any one of embodiments 38-43, wherein    the subject's risk of developing future carcinogenesis after    exposure to ionizing radiation is reduced.-   45. The method according to any one of embodiments 38-44, wherein    the toxicity is one or more of bone marrow toxicity, central nervous    system toxicity, immunological toxicity, gastrointestinal toxicity,    neurotoxicity, nephrotoxicity, ototoxicity, cardiotoxicity,    hepatoxicity, cutaneous toxicity, alopecia mucositis, xerostomia,    infertility, peripheral neuropathy, pulmonary toxicity or renal    toxicity.-   46. The method of embodiment 45, wherein the toxicity is a late    onset toxicity.-   47. The method according to any one of embodiments 38-42, wherein    the condition is acute radiation syndrome.-   48. The method according to embodiment 47, wherein one or more    symptoms of acute radiation syndrome is prevented, eliminated or    alleviated.-   49. The method according to embodiment 48, wherein the acute    radiation syndrome symptom is one or more symptom selected from the    group consisting of nausea, vomiting, headache, diarrhea, loss of    appetite, fatigue, fever, skin damage and hair loss.-   50. The method according to any one of embodiments 38-49, wherein    the pharmaceutical composition stimulates bone marrow production.-   51. The method according to any one of embodiments 38-43, wherein    the condition is a cognitive disorder selected from Alzheimer's    disease or dementia.-   52. The method according to any one of embodiments 38-43, wherein    the condition is premature aging.-   53. The method according to any one of embodiments 38-43, wherein    the condition is selected from the group consisting of    COVID-19-associated cytokine storm, COVID-19-associated multisystem    inflammatory syndrome in children (MIS-C), and post-COVID-19    SARS-CoV-2-induced autoimmunity.-   54. The method according to any one of embodiments 38-43, wherein    the disease or condition is associated with oxidative stress.-   55. The method according to embodiment 54, wherein the disease or    condition is renal ischemia, myocardial ischemia, spinal cord    ischemia and reperfusion injury, Alzheimer's disease, Parkinson's    disease, rheumatoid arthritis myocardial infarction, cardiovascular    disease, septic shock, chronic inflammation, Friedreich ataxia,    Leber's hereditary optic neuropathy, myoclonus epilepsy, ragged red    fiber disease, Mitochondrial Encephalopathy, Lactic Acidosis and    Stroke (MELAS), radiation-induced cognitive decline,    COVID-19-associated cytokine storm, COVID-19-associated multisystem    inflammatory syndrome in children (MIS-C), or post-COVID-19    SARS-CoV-2-induced autoimmunity.-   56. The method according to any one of embodiments 38-55, wherein    the compound or the pharmaceutical composition is administered prior    to, during, or after the subject has been or will be exposed to    ionizing radiation.-   57. A method of protecting normal tissues in a subject against    toxicities associated with radiation therapy with minimal effect on    the tumor response to those treatments, the method comprising    administering to said subject a therapeutically effective amount of    a compound according to any one of embodiments 1-20, or a    pharmaceutically acceptable salt, solvate, hydrate, or polymorph    thereof or a solvate, hydrate, or polymorph of the pharmaceutically    acceptable salt, or of a pharmaceutical composition according to any    one of embodiments 24-37.-   58. The method according to embodiment 57, wherein the radiation    therapy is gamma radiation, X-radiation, proton beam radiation,    electron beam radiation, gamma radiation from cobalt-60 decay, or in    the form of a radiopharmaceutical.-   59. The method according to embodiment 57 or 58, wherein the    compound or the pharmaceutical composition is administered before,    concurrently, separately, sequentially with, or after a radiation    therapy.-   60. The method according to any one of embodiments 57-59, wherein    the radiation therapy is combined with a chemotherapeutic agent or    immunotherapy.-   61. The method according to embodiment 60, wherein the immunotherapy    is selected from the group consisting of immune checkpoint    inhibitors, T-cell transfer therapy, monoclonal antibodies,    treatment vaccines and immune system modulators.-   62. The method according to embodiment or 60, wherein the    chemotherapeutic agent is selected from cyclophosphamide,    ifosfamide, etoposide, oxaliplatin, cisplatin, carboplatin,    mechlorethamine, melphalan, chlorambucil, cyclophosphamide,    streptozocin, carmustine, lomustine, bleomycin, busulfan,    bendamustine, dacarbazine, doxorubicin, daunoubicin, temozolomide,    thiotepa, altretamine, procarbaine, hexamethylmelamine, teniposide    or mitoxantrone.-   63. A method of protecting normal tissues in a subject against    toxicities associated with chemotherapy without adversely affecting    the tumor response to those treatments, the method comprising    administering to said subject a therapeutically effective amount of    a compound according to any one of embodiments 1-20, or a    pharmaceutically acceptable salt, solvate, hydrate, or polymorph    thereof or a solvate, hydrate, or polymorph of the pharmaceutically    acceptable salt, or of a pharmaceutical composition according to any    one of embodiments 24-37.-   64. The method according to embodiment 63, wherein the    chemotherapeutic agent is selected from cyclophosphamide,    ifosfamide, etoposide, oxaliplatin, cisplatin, carboplatin,    mechlorethamine, melphalan, chlorambucil, cyclophosphamide,    streptozocin, carmustine, lomustine, bleomycin, busulfan,    bendamustine, dacarbazine, doxorubicin, daunoubicin, temozolomide,    thiotepa, altretamine, procarbaine, hexamethylmelamine, teniposide    or mitoxantrone.-   65. The method according to embodiment 63 or 64, wherein the    compound or the pharmaceutical composition is administered before,    concurrently, separately, sequentially with, or after a    chemotherapeutic agent.-   66. The method according to any of embodiments 63-65, wherein the    chemotherapy is combined with immunotherapy.-   67. The method according to embodiment 66, wherein the immunotherapy    is selected from the group consisting of immune checkpoint    inhibitors, T-cell transfer therapy, monoclonal antibodies,    treatment vaccines and immune system modulators.-   68. A method of reducing the risk of secondary tumor induction in a    subject being treated with radiation therapy, the method comprising    administering to said subject a therapeutically effective amount of    a compound according to any one of embodiments 1-20, or a    pharmaceutically acceptable salt, solvate, hydrate, or polymorph    thereof or a solvate, hydrate, or polymorph of the pharmaceutically    acceptable salt, or of a pharmaceutical composition according to any    one of embodiments 24-37.-   69. The method according to embodiment 68, wherein the radiation    therapy is gamma radiation, X-radiation, proton beam radiation or    gamma radiation from cobalt-60 decay, or from a radiopharmaceutical.-   70. The method according to embodiment 68 or 69, wherein the    compound or the pharmaceutical composition is administered before,    concurrently, separately, sequentially with, or after a radiation    therapy.-   71. The method according to any one of embodiments 68-70, wherein    the radiation therapy is combined with a chemotherapeutic agent or    immunotherapy.-   72. The method according to embodiment 71, wherein the immunotherapy    is selected from the group consisting of immune checkpoint    inhibitors, T-cell transfer therapy, monoclonal antibodies,    treatment vaccines and immune system modulators.-   73. The method according to embodiment or 71, wherein the    chemotherapeutic agent is selected from cyclophosphamide,    ifosfamide, etoposide, oxaliplatin, cisplatin, carboplatin,    mechlorethamine, melphalan, chlorambucil, cyclophosphamide,    streptozocin, carmustine, lomustine, bleomycin, busulfan,    bendamustine, dacarbazine, doxorubicin, daunoubicin, temozolomide,    thiotepa, altretamine, procarbaine, hexamethylmelamine, teniposide    or mitoxantrone.-   74. A method of reducing the risk of secondary tumor induction in a    subject being treated with chemotherapy, the method comprising    administering to said subject a therapeutically effective amount of    a compound according to any one of embodiments 1-20, or a    pharmaceutically acceptable salt, solvate, hydrate, or polymorph    thereof or a solvate, hydrate, or polymorph of the pharmaceutically    acceptable salt, or of a pharmaceutical composition according to any    one of embodiments 24-37.-   75. The method according to embodiment 74, wherein the    chemotherapeutic agent is selected from cyclophosphamide,    ifosfamide, etoposide, oxaliplatin, cisplatin, carboplatin,    mechlorethamine, melphalan, chlorambucil, cyclophosphamide,    streptozocin, carmustine, lomustine, bleomycin, busulfan,    bendamustine, dacarbazine, doxorubicin, daunoubicin, temozolomide,    thiotepa, altretamine, procarbaine, hexamethylmelamine, teniposide    or mitoxantrone.-   76. The method according to embodiment 74 or 75, wherein the    compound or the pharmaceutical composition is administered before,    concurrently, separately, sequentially, or after with a    chemotherapeutic agent.-   77. The method according to any of embodiments 74-76, wherein the    chemotherapy is combined with immunotherapy.-   78. The method according to embodiment 77, wherein the immunotherapy    is selected from the group consisting of immune checkpoint    inhibitors, T-cell transfer therapy, monoclonal antibodies,    treatment vaccines and immune system modulators.-   79. The method of any one of embodiments 38 or 57-78, wherein the    subject has cancer and the cancer is hematological cancer, bone    cancer, leukemia, lymphoma, myeloma, rectal cancer, colorectal    cancer, breast cancer, ovarian cancer, prostate cancer,    androgen-dependent prostate cancer, lung cancer, mesothelioma, head    and neck cancer, esophageal cancer, gastric cancer, pancreatic    cancer, gastrointestinal cancer, renal cell cancer, testicular    cancer, germ cell cancer, glioma, cancers of the central nervous    system or any other primary or solid tumor.-   80. A method of reducing the risk of tumor induction in a subject    who has been exposed to, is being exposed to, or will be exposed to    ionizing radiation, the method comprising administering to said    subject a therapeutically effective amount of a compound according    to any one of embodiments 1-20, or a pharmaceutically acceptable    salt, solvate, hydrate, polymorph or combination thereof, or of a    pharmaceutical composition according to any one of embodiments    24-37.-   81. The method according to embodiment 80, wherein the source of the    ionizing radiation is nuclear warfare, a nuclear reactor, air    travel, or space travel.-   82. The method according to embodiment 81, wherein the source of the    ionizing radiation is space travel, and the radiation is from one or    more of galactic cosmic rays, chronic solar radiation, solar flares    or coronal mass ejections.-   83. The method according to embodiment 80, wherein the source of    ionizing radiation is radiation therapy.-   84. The method of any one of embodiments 80-83, wherein the ionizing    radiation exposure is acute radiation exposure.-   85. The method of any one of embodiment 80-83, wherein the ionizing    radiation exposure is chronic radiation exposure.-   86. A method of slowing the aging process in a subject, wherein the    method comprises administering a compound according to any one of    embodiments 1-20, or the pharmaceutical composition according to any    one of embodiments 24-37.-   87. The method according to embodiment 86, wherein the health span    of the subject is increased.-   88. A method of treating a disease or condition in a subject in need    thereof comprising administering a compound according to any one of    embodiments 1-20, or the pharmaceutical composition according to any    one of embodiments 24-37.-   89. The method according to embodiment 88, wherein the disease or    condition is associated with oxidative stress.-   90. The method according to embodiment 88 or 89, wherein the disease    or condition is renal ischemia, myocardial ischemia, spinal cord    ischemia and reperfusion injury, Alzheimer's disease, Parkinson's    disease, rheumatoid arthritis myocardial infarction, cardiovascular    disease, septic shock, chronic inflammation, Friedreich ataxia,    Leber's hereditary optic neuropathy, myoclonus epilepsy, ragged red    fiber disease,

Mitochondrial Encephalopathy, Lactic Acidosis and Stroke (MELAS),radiation-induced cognitive decline, COVID-19-associated cytokine storm,COVID-19-associated multisystem inflammatory syndrome in children(MIS-C), or post-COVID-19 SARS-CoV-2-induced autoimmunity.

Definitions and General Techniques

Unless otherwise defined herein, scientific and technical terms used inthis application shall have the meanings that are commonly understood bythose of ordinary skill in the art. In case of conflict, the presentspecification, including definitions and claims, will control.

Throughout this specification and embodiments, the word “comprise,” orvariations such as “comprises” or “comprising,” will be understood toimply the inclusion of a stated integer or group of integers but not theexclusion of any other integer or group of integers.

The term “including” or “includes” is used to mean “including but notlimited to.” “Including” and “including but not limited to” are usedinterchangeably.

Any example(s) following the term “e.g.” or “for example” is not meantto be exhaustive or limiting.

Unless otherwise required by context, singular terms shall includepluralities and plural terms shall include the singular.

The articles “a”, “an” and “the” are used herein to refer to one or tomore than one (i.e., to at least one) of the grammatical object of thearticle.

Notwithstanding that the disclosed numerical ranges and parameters areapproximations, the numerical values set forth in the specific examplesare reported as precisely as possible. Any numerical value, however,inherently contains certain errors necessarily resulting from thestandard deviation found in their respective testing measurements.Moreover, all ranges disclosed herein are to be understood to encompassany and all subranges subsumed therein. For example, a stated range of“1 to 10” should be considered to include any and all subranges between(and inclusive of) the minimum value of 1 and the maximum value of 10;that is, all subranges beginning with a minimum value of 1 or more,e.g., 1 to 6.1, and ending with a maximum value of 10 or less, e.g., 5.5to 10.

Where aspects or embodiments are described in terms of a Markush groupor other grouping of alternatives, the present application encompassesnot only the entire group listed as a whole, but each member of thegroup individually and all possible subgroups of the main group, andalso the main group absent one or more of the group members. The presentapplication also envisages the explicit exclusion of one or more of anyof the group members in the disclosure.

Each embodiment of this disclosure may be taken alone or in combinationwith one or more other embodiments of this disclosure.

Exemplary methods and materials are described herein, although methodsand materials similar or equivalent to those described herein can alsobe used in the practice or testing of the various aspects andembodiments. The materials, methods, and examples are illustrative onlyand not intended to be limiting.

In order for the disclosure to be more readily understood, certain termsare first defined. These definitions should be read in light of theremainder of the disclosure as understood by a person of ordinary skillin the art. Unless defined otherwise, all technical and scientific termsused herein have the same meaning as commonly understood by a person ofordinary skill in the art. Additional definitions are set forththroughout the detailed description.

The term “about”, as used herein, refers to a value or parameter thatincludes (and describes) embodiments that are directed to that value orparameter per se. For example, description referring to “about X”includes description of “X”. Numeric ranges are inclusive of the numbersdefining the range. Unless specified otherwise, the term “about” whenused in the context of a dosage of a compound to be administered to apatient, permits a variation of ±10% of a given value or range. Forexample, about 50 μM would include a range of 45 μM to 55 μM.

The term “derivative” is used herein to refer to the chemicalmodification of a parent compound. Chemical modifications of a compoundcan include, for example, replacement of hydrogen by an alkyl or arylgroup. Many other modifications are possible.

The term “analogue” is used herein to refer to a compound having asimilar structure to that of another compound but differing from it withrespect to a certain component. The analogue may differ from the parentcompound by virtue of one or more atoms, functional groups orsubstructures.

The term “substituted”, as used herein, means that any hydrogen on thedesignated atom or moiety or group can be replaced with a selection fromthe indicated substituent group, provided that the normal valency of thedesignated atom, moiety or group is not exceeded, and that thesubstitution results in a stable compound.

The term “alkyl”, as used herein, refers to a saturated, branched- orstraight-chain alkyl group. Examples of alkyl groups include, but arenot limited to, methyl, ethyl, propyl, iso-propyl, tent-butyl,isopentyl, neopentyl and the like. In some embodiments, alkyl as usedherein is (C1-C6)alkyl. In some embodiments, alkyl as used hereininclude an alkyl that is substituted with 0-3 substituents selected fromthe group consisting of —OH, —SH, —SCH₃, —C(O)NH₂, —C(O)OH, —NH₂ and—NH—C(═NH)NH₂. In some embodiments,

The term “alkenyl”, as used herein, refers to an unsaturated, branched-or straight-chain aliphatic group containing at least one carbon-carbondouble bond. Examples of alkenyl groups include, but are not limited to,ethenyl, propenyl, iso-propenyl, butenyl, pentenyl, hexenyl and thelike. In some embodiments, alkenyl as used herein includes(C2-C6)alkenyl.

The term “alkynyl”, as used herein, refers to an unsaturated, branched-or straight-chain aliphatic group containing at least one carbon-carbontriple bond. Examples of alkynyl groups include, but are not limited to,ethynyl, propynyl, iso-propynyl, butynyl, pentynyl, hexynyl and thelike.

The term “aliphatic” as used herein refers to a straight chained orbranched alkyl, alkenyl or alkynyl. It is understood that alkenyl oralkynyl embodiments need at least two carbon atoms in the aliphaticchain. Aliphatic groups typically contain from 1 (or two for alkenyl oralkynyl groups) to 12 carbons, such as from 2 to 4 carbons.

As used herein, the carbon atom designations may have the indicatedinteger and any intervening integer. For example, the number of carbonatoms in a (C1-C3)alkyl group is 1, 2 or 3.

The term “aryl” as used herein refers to a monocyclic or bicycliccarbocyclic aromatic ring system. Aryl as used herein includes a(C6-C12)aryl-. For example, aryl as used herein can be a C6-C10monocyclic or C8-C12 bicyclic carbocyclic aromatic ring system. In someembodiments, aryl as used herein can be a (C6-C10)aryl. Phenyl (or Ph)is an example of a monocyclic ring system. Bicyclic aromatic ringsystems include systems wherein both rings are aromatic, e.g., naphthyl,and systems wherein only one of the two rings is aromatic, e.g.,tetralin.

The term “heteroaryl” as used herein refers to a monocyclic or bicyclicaromatic ring system having at least one heteroatom, selected oxygen(O), sulfur (S) or nitrogen (N), in a chemically stable arrangement.Heteroaryl as used herein includes a 5- to 10-membered heteroaryl having1-4 heteroatoms independently selected from O, N or S. In someembodiments, heteroaryl as used herein can be a 5- to 10- memberedheteroaryl having 1-4 heteroatoms independently selected from O, N, orS. For example, heteroaryl as used herein can be a 5- to 10- memberedmonocyclic or bicyclic aromatic ring system having 1 to 4 heteroatomsselected from O, N, or S in one or both rings in a chemically stablearrangement. As used herein, heteroaryl refers to a monocyclic aromaticring having 1-4 heteroatoms selected from O, N or S. As used herein,heteroaryl refers to a bicyclic aromatic ring system wherein one or bothrings are aromatic. Examples of monocyclic heteroaryls include, but arenot limited to, 6-membred ring substituents such as pyridinyl,pyrazinyl, pyrimidinyl and pyridazinyl; and 5-membered heteroaryls suchas triazolyl, imidazolyl, furanyl, isoxazolyl, isothiazolyl, 1,2,3-,1,2,4, 1,2,5 or 1,3,4-oxadiazolyl, oxazolyl, thiazolyl, isothiazolyl,and pyrazolyl. Examples of bicyclic heteroaryl groups include but arenot limited to indolyl, isoindole, benzofuranyl, benzimidazolyl,benzothienyl, benzoxadiazolyl, benzothiazolyl, isobenzothiofuranyl,benzothiofuranyl, benzisoxazolyl, benzoxazolyl, benzodioxolyl,isobenzothiofuranyl, benzothiofuranyl, quinolinyl, isoquinolinyl,cinnolinyl, quinazolinyl, oxochromanyl, 1,4-benzoxazinyl,1,2,3,4-tetrahydroquinolinyl, 1,2-dihydroquinolinyl, and indolinyl. Insome embodiments, heteroaryl as used herein includes a 5- or 6-memberedheteroaryl. In some embodiments, heteroaryl as used herein includes a 5-or 6-membered heteroaryl that is fused to a 6-membered heterocycloalkyl.

As used herein, the term “cycloalkyl” refers to a monocyclic,spirocyclic, fused or bridged bicyclic carbocyclic ring system that isnot aromatic. A cycloalkyl may be a monocyclic ring, including but notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl. A cycloalkyl may be a fused or a bridgedbicyclic group. Fused bicyclic groups include, for example,bicyclo[1.1.0]butanyl, bicyclo[2.1.0]pentanyl, bicyclo[2.2.0]hexanyl,bicyclo[3.1.0]hexanyl and the like. Bridged bicyclic groups include, forexample, bicyclo[2.2.1]heptanyl and bicyclo[1.1.1]pentanyl. Examples ofspirocyclic cycloalkyl groups include, but are not limited to,spiro[5.5]undecanyl, spiropentadienyl, spiro[4.5]decanyl andspiro[3.6]decanyl. Also included in the definition of cycloalkyl areunsaturated non-aromatic cycloalkyls, including, but not limited to,cyclohexenyl, cyclohexadienyl, cyclopentenyl, cycloheptenyl,cyclooctenyl, cyclootadienyl and the like. In some embodiments,cycloalkyl as used herein includes a (C5-C6)cycloalkyl. In someembodiments, cycloalkyl as used herein includes a (C3-C7)cycloalkyl. Insome embodiments, cycloalkyl as used herein includes an—O—(C3-C7)cycloalkyl

The term “heterocycloalkyl” as used herein refers to a monocyclic,spirocyclic, fused or bridged bicyclic non-aromatic ring system havingat least one heteroatom selected from O, N or S (or P in the case offormula I, where R¹ and R², one of which is CH₂ or the other is CH₂CH₂,are taken together with the —O—P—O linkage to form a6-membered-heterocycloalkyl ring) in a chemically stable arrangement.For example, heterocycloalkyl as used herein can be a 3- to 10- memberedmonocyclic or 8- to 12-membered bicyclic non-aromatic ring system having1 to 4 heteroatom or heteroatom groups in each ring selected from O, Nor S in a chemically stable arrangement. In some embodiments,heterocycloalkyl as used herein can be a 3- to 10- membered heterocycle-having 1-4 heteroatoms independently selected from O, N, or S. In someembodiments, heterocycloalkyl as used herein includes —O—(C1-C6)alkyl.In some embodiments, heterocycloalkyl as used herein includes-C(O)0(C1-C3)alkyl. In some embodiments, heterocycloalkyl as used hereinincludes a 5- or 6-membered heterocycloalkyl. In some embodiments,heterocycloalkyl as used herein includes a 5- to 8-memberedheterocycloalkyl. In some embodiments, heterocycloalkyl as used hereinincludes an —O—(5- to 8-membered)heterocycloalkyl. In some embodiments,heterocycloalkyl as used herein includes a 5- to 10-memberedheterocycloalkyl. In a bicyclic non-aromatic ring system, one or bothrings may contain said heteroatom. A bicyclic heterocycloalkyl caninclude groups wherein both rings are non-aromatic. A bicyclicheterocycloalkyl can include groups wherein only one of the rings isnon-aromatic, and the other is aromatic. Examples of heterocycloalkylrings include, but are not limited to, 2-tetrahydrofuranyl,3-tetrahydrouranyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiphenyl,2-morpholino, 3-morpholino, 2-thiomorpholino, 3-thiomorpholino,4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl,1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl,3-tetrahydropiperazinyl, 1-piperadinyl, 2-piperidinyl, 3-piperdinyl,1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl,1-piperidinyl, 2-piperidiinyl, 3-piperidinyl, 4-piperidinyl,2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl,2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, indolinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolane, andbenzodithiane. Examples of spirocyclic heterocycloalkyl groups include,but are not limited to 1,4,6-triazaspiro[4.4]nonanyl,2-oxaspiro[4.4]nonanyl, 3-oxaspiro[5.5]undec-8-enyl,7-oxaspiro[4.5]decanyl, 7-oxa-1-azaspiro[4.5]decanyl, and6-oxaspiro[4.5]dec-7-enyl. Also included in the definition ofheterocycloalkyl are unsaturated non-aromatic heterocycloalkyl groups.Examples of non-aromatic heterocycloalkyl groups include, but are notlimited to, 1,2-dihydroazetyl, 2,5-dihydro-1H-pyrrolyl,3,6-dihydro-2H-pyranyl, 2,5-dihydrofuranyl, 2,3-dihydrofuranyl, and4H-pyranyl.

The term “-(4- to 20-membered)heteroalkyl” refers to a saturatedstraight chain or branched chain alkyl group wherein 1 to 6 of the atomsare a heteroatom or heteroatom group selected from —O—, —S— and —NH— andthe remaining atoms are carbon. In some embodiments, the (4- to20-membered)heteroalkyl group has 1 to 6 heteroatoms selected from —O—and —S—. In some embodiments, the (4- to 20-membered)heteroalkyl grouphas 1 to 6 —O— atoms. In some embodiments, the (4- to20-membered)heteroalkyl is a polyethylene glycol (PEG) derivative,having the formula —[(CH₂)₂O]_(x)—R, wherein x is an integer between 1and 10 and R is hydrogen or a (C1-C6)alkyl group (e.g., methyl, ethyl,propyl and the like). In some embodiments, the (4- to20-membered)heteroalkyl group is a PEG derivative, having the formula,[(CH₂)_(y)O]_(z)—R, —CH₂—O—[(CH₂)_(y)O]_(z)—R, or —O—[(CH₂)_(y)O]_(z)—R,wherein y is an integer between 1 and 4; z is an integer between 1 and10; and R is hydrogen or a (C1-C6)alkyl group (e.g., methyl, ethyl,propyl, iso-propyl, butyl, tent-butyl, pentyl, neopentyl, hexyl and thelike). In some embodiments, the (4- to 20-membered)heteroalkyl includesa —O—(C1-C6)alkyl.

The term “pharmaceutically acceptable salt” refers to salts which retainthe biological effectiveness and properties of the compounds of thisdisclosure and which are not biologically or otherwise undesirable. Insome embodiments, the compounds of this disclosure are capable offorming acid and/or base salts by virtue of the presence of amino,thiol, and/or phosphate groups or groups similar thereto.Pharmaceutically acceptable salts can be prepared from inorganic andorganic bases or acids.

The term “ionizing radiation” refers to radiation with enough energy toremove electrons from atoms and molecules that it interacts with. Formsof ionizing radiation include alpha, beta and neutron particles, gammaradiation, X-radiation and high energy UV-radiation.

The term “reactive oxygen species” or “ROS” refers to the compounds thatare formed when aqueous solutions are exposed to ionizing radiation.Exposure of living tissues to ionizing radiation leads to the formationof ROS which are involved in the initiation and propagation of freeradical chain reactions which can be highly damaging to living tissues.Examples of ROS include, but are not limited to superoxide, hydrogenperoxide, hydroxyl, peroxyl, and alkoxyl radicals.

The term “acute onset toxicity” refers to an ionizing toxicity where thesymptoms associated with radiation injury present within minutes, hours,days or weeks after exposure to ionizing radiation. In some embodiments,the symptoms associated with acute onset toxicity occur within 10minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 2hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10hours, 11 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6days, 7 days, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks or11 weeks after exposure to ionizing radiation.

The term “late onset toxicity” refers to an ionizing toxicity whereinthe symptoms associated with radiation injury do not present until aftera latency period. An example of late onset toxicity includes, but is notlimited to, the development of cardiotoxicity, in a subject beingtreated with ionizing radiation for breast cancer, several months oryears after completion of the treatment. In some embodiments, thesymptoms associated with a late onset toxicity occur after a latencyperiod of several months to years after exposure to ionizing radiation.In some embodiments, the symptoms associated with a late onset toxicityoccur 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9months, 10 months, 11 months, 12 months, 1.5 years, 2 years, 2.5 yearsor 3 years after exposure to ionizing radiation.

The term “chronic radiation exposure” refers to long-term or cumulativeexposure to low-levels of ionizing radiation. Examples of chronicradiation exposure include, but are not limited to, exposure to ionizingradiation during air travel (e.g., flight crews and passengers), spacetravel, radiotherapy, or during the decommissioning and/or installationof nuclear reactors (e.g., naval vessels and nuclear energy plants).

The term “chronic radiation syndrome” refers to a condition that occursin a subject who has experienced chronic radiation exposure for a periodof about 3 years or more. Symptoms of chronic radiation syndromeinclude, but are not limited to, sleep and appetite disturbance,generalized weakness and fatigability, altered mood, poor memory,reduced concentration, vertigo, ataxia, parasthesia, headache, syncopalepisodes, hot flashes and chills.

The term “acute radiation exposure” refers to short-term exposure tohigh-levels of ionizing radiation. Examples of acute radiation exposureinclude, but are not limited to, exposure to ionizing radiation afternuclear reactor accidents, nuclear warfare (e.g., nuclear bomb), nuclearterrorism (e.g., explosive devices that disperse radioactive material(dirty bombs) or space travel.

The term “acute radiation syndrome” or “ARS” refers to a condition thatoccurs in a subject who has experienced acute radiation exposure. Themain manifestations of ARS include bone marrow syndrome,gastrointestinal syndrome and cardiovascular syndrome. There are threerecognized phases of ARS including a prodromal phase, latent stagephase, and the overt systemic illness phase. The symptoms associatedwith the prodromal stage can occur a few hours of radiation exposure, orlater. The symptoms include nausea, vomiting, anorexia, and diarrhea,and may last for a few minutes up to several days. In the latent stageof ARS, the subject looks and feels healthy for a period lasting for afew hours up to a few weeks. The overt systemic illness phase ischaracterized by various symptoms that are based on one or more specificsyndromes, i.e., bone marrow syndrome, gastrointestinal syndrome,cutaneous and cardiovascular syndrome.

The term “treating” refers to reversing, alleviating, ameliorating orslowing the progression, of one or more symptoms associated with acondition, toxicity, disease or disorder described herein.

The term “preventing” refers to inhibiting, avoiding, stopping orslowing the development of one or more symptoms associated with acondition, toxicity, disease or disorder described herein.

As used herein, the term “health span” refers to the period of timeduring which a subject is alive and healthy (e.g., free of seriousillness, chronic diseases and/or disabilities of aging).

As used herein, the term “compound” refers to compounds having astructure according to any one of formulae I, II, III, IV, V, VI or VII,and their pharmaceutically acceptable salts, isomers, solvates,hydrates, or polymorphs thereof, or a solvate, hydrate, or polymorph ofthe pharmaceutically acceptable salt.

As used herein, the term “prodrug” refers to a compound that isadministered to a subject in need thereof in its inactive form, that isfurther metabolized by the body in vivo (e.g., by the action of anenzyme) to produce its active form. In some embodiments, the compoundsof the disclosure are double prodrugs, and are metabolized by twodifferent metabolic pathways (e.g., two different enzymatic reactions)to produce the active compound. Without wishing to be bound by theory,the prodrugs of the disclosure are more lipophilic than the parentcompounds (i.e., the drug in its active form). The enhancedlipophilicity of the prodrugs and double prodrugs according to thedisclosure improves their bioavailability as compared to the parentcompound. Additionally, without wishing to be bound by theory, theprodrugs and double prodrugs of this disclosure are more resistant tooxidation as compared to the active form. Therefore, the prodrugs anddouble prodrugs of this disclosure often have a longer shelf-life.Prodrugs and double prodrugs according to the disclosure have an A groupthat is characterized by Moiety A¹, Moiety A² or Moiety A³ as describedherein.

Compounds of the Disclosure

Ionizing radiation-induced ROS can further combine with lipids to formtoxic, reactive alpha-ketoaldehydes (Wondrak, G. T. et al., Biochem.Pharmacol. 2002, Vol. 63, pp 361-373). Without wishing to be bound bytheory, the compounds according to the disclosure may react withalpha-ketoaldehydes to form less reactive and less toxic adducts.Accordingly, the compounds according to this disclosure may help protecttissues from ionizing radiation (e.g., x rays, gamma rays, or proteinbeam), radiation inherent in radiotherapy, or ROS in chemotherapy evenafter the damaging ROS have damaged cellular macromolecules, byinactivating alpha-ketoaldehydes.

Amifostine (3-[3-(methylamino)propylamino]propylsulfanylphosphonic acid)is an FDA approved aminothiophosphonate radioprotector that isadministered intravenously (and subcutaneously off label). It isapproved for use in reducing renal toxicity associated with repeatedexposure to the chemotherapeutic agent, cisplatin, in subjects withovarian cancer, and to reduce xerostomia in subjects undergoingpost-operative radiation treatment for head and neck cancer. It lacksefficacy as a radioprotector when administered orally.

Amifostine is dephosphorylated by alkaline phosphatase in healthytissues to its active thiol metabolite (2-[(3-aminopropyl)amino]ethanethiol).

A number of adverse side-effects are associated with the administrationof Amifostine including hypotension, nausea and vomiting, hypocalcemia,flushing, chills, malaise, pyrexia, rash, dizziness, somnolence,diarrhea, diplopia and blurred vision, and in rare cases, seizures andsyncope. Injection site reactions have also been observed.

The aminothiol, 3-(methylamino)-2-((methylamino)methyl)propane-1-thiol(PrC-210):

has also been developed as a radioprotector, and has demonstratedradioprotective properties when administered topically and orally inpreclinical studies. PrC-210 is reported to be associated with less sideeffects than Amifostine (see Peebles D D, Soref C M, Copp R R, ThunbergA L, Fahl W E. ROS-scavenger and radioprotective efficacy of the newPrC-210 aminothiol. Radiat Res. 2012; 178(1):57-68.doi:10.1667/rr2806.1).

The free thiol group of PrC-210, however, may be susceptible tooxidation which can adversely affect its shelf life. Additionally,PrC-210 has not been shown to preferentially protect healthy tissuesover tumor tissues. Accordingly, there is a need to developradioprotective agents that are sufficiently stable, and that protecthealthy tissues over tumor tissues for use in conjunction withradiotherapy and/or chemotherapy.

The compounds of this disclosure are novel aminothiols,aminothiophosphonate and aminothioester radioprotectors or prodrugs ordouble prodrugs of such protectors. They are suitable for oraladministration and have fewer side effects when administered to asubject in need thereof to protect normal tissues against ionizing ortherapeutic radiation or chemotherapy. The compounds of this disclosureinclude {[3-(methylamino)-2-[(methylamino)methyl] propyl]sulfanyl}phosphonic acid (PrC-210-PT) and derivatives or analogues thereof aswell as prodrugs and double prodrugs thereof. See, e.g., the compoundsof formulae I-VII.

In some embodiments, the compounds of the disclosure are characterizedby a tertiary alkyl thiol, or are prodrugs thereof (i.e., compounds thatare metabolized to tertiary alkyl thiols). Without wishing to be boundby theory, those compounds are less toxic than primary thiols due to theadded steric hinderance around the reactive thiol. The steric hinderanceprevents the thiol from interacting with macromolecules associated withtoxicity, but will still allow detoxification of ROS and ketoaldehydes.

In some embodiments, the compound according to this disclosure has astructure according to formula I:

-   or a pharmaceutically acceptable salt, solvate, hydrate, or    polymorph thereof, or a solvate, hydrate, or polymorph of the    pharmaceutically acceptable salt, wherein;-   each R⁰ is independently hydrogen, (C1-C3)alkyl, or —SH;-   A is selected from hydrogen, Moiety A¹, Moiety A² or Moiety A³:

-   -   wherein each of R¹ and R² is independently selected from the        group consisting of hydrogen, —(CH(R⁶))—O—C(O)R¹⁰,        —(CH(R⁶))_(m)—S—C(O)R¹⁰ and —CH₂—(C(R¹¹)₂)—C(O)—CH₂—S—C(O)R¹⁰; m        is an integer selected from the group consisting of 0, 1, 2, 3,        and 4;or        -   R¹ and R², one of which is CH₂ or the other is CH₂CH₂, taken            with the —O—P—O-linkage to which they are attached form a            6-membered heterocycloalkyl ring that is substituted with            1-2 R^(a) and 0-3 R^(b);    -   wherein each R^(a) is independently hydrogen, (C1-C6)alkyl,        (C6-C10)aryl- or a 5- to 10-membered heteroaryl-, wherein said        alkyl, aryl and heteroaryl is substituted with 0-3 R^(c),        provided that at least one R^(a) group is (C6-C10)aryl- or a 5-        to 10-membered heteroaryl-;    -   wherein when present, each R^(b) is —(C1-C3)alkyl;    -   wherein each R^(c) is independently selected from the group        consisting of halogen, (C1-C3)alkyl, —CN, —O—(C1-C3)alkyl,        —S—(C1-C3)alkyl, —C(O)O—(C1-C3)alkyl, —N(R′)₂, —CF₃ and —OCF₃;    -   wherein each R⁶ is independently hydrogen or (C1-C3)alkyl;    -   wherein each R¹⁰ is selected from the group consisting of        —(C1-C6)alkyl, —O—(C1-C6)alkyl, —O—(C6-C10)aryl, —(C6-C10)aryl,        (5- to 10-membered)heteroaryl, (4- to        10-membered)heterocycloalkyl, (C3 -C10)cycloalkyl, —O-(5- to        10-membered)heteroaryl, —O-(4- to 10-membered)heterocycloalkyl,        —O—(C3-C10)cycloalkyl, —O—(4- to 20-membered)heteroalkyl, -(4-        to 20-membered)heteroalkyl, —[(CH₂)_(y)O]_(z)—R,        —CH₂—O—[(CH₂)_(y)O]_(z)—R and —O—[(CH₂)_(y)O]_(z)—R, wherein        each of said heteroalkyl, heterocycloalkyl, and heteroaryl        independently have 1-6 oxygen atoms, wherein y is an integer        between 1 and 4, wherein z is an integer between 1 and 10,        wherein R is hydrogen or (C1-C6)alkyl, and wherein each R¹⁰ is        independently substituted with 0-3 R_(c);    -   wherein each R¹¹ is independently selected from the group        consisting of hydrogen, —(C1-C6)alkyl, —CH₂—O—C(O)R″, —C(O)—OR″,        -(4- to 20-membered)heteroalkyl, —O—(4- to        20-membered)heteroalkyl, —[(CH₂)_(y)O]_(z)—R,        —CH₂—O—[(CH₂)_(y)O]_(z)—R and —O—[(CH₂)_(y)O]_(z)—R, wherein        each of said heteroalkyl independently has 1-6 oxygen atoms,        wherein y is an integer between 1 and 4, wherein z is an integer        between 1 and 10, and wherein R is hydrogen or (C1-C6)alkyl;

-   -   wherein W and Y are independently selected from N or CH;    -   wherein R³ is hydrogen, halogen, (C1-C6)alkyl,        (C3-C7)cycloalkyl, (5- to 8-membered)heterocycloalkyl,        —O—(C1-C6)alkyl, —O—(C3-C7)cycloalkyl, —O—(5- to        8-membered)heterocycloalkyl, (C2-C6)alkenyl, —CH₂OH, phenyl, (5-        to 6-membered)heteroaryl, or (5- to 6-membered)heterocycloalkyl,        wherein R³ is substituted with 0-3 substituents selected from        the group consisting of halogen, oxo, —CN, —(C1-C6)alkyl,        —O—(C1-C6)alkyl, and —C(O)O(C1-C3)alkyl;    -   wherein R⁴ is hydrogen, —CN, (C1-C6)alkyl, —O—(C1-C6)alkyl,        (C2-C6)alkenyl or —CH₂OH;    -   or R⁴ and R³ are taken together with the carbon atoms to which        they are attached to form a (C5-C6)cycloalkyl, (C6-C10)aryl, (5-        to 10-membered)heterocycloalkyl or (5- to        10-membered)heteroaryl;    -   wherein R⁵ is hydrogen, halogen, (C1-C6)alkyl or        —O—(C1-C6)alkyl; or    -   R⁵ and R⁴ are taken together with the carbon atoms to which they        are attached to form a (C5-C6)cycloalkyl, phenyl, (5- or        6-membered)heterocycloalkyl, or (5- or 6-membered)heteroaryl;    -   wherein each R⁶ is independently hydrogen or (C1-C3)alkyl;    -   wherein R¹⁴ is —(C1-C6)alkyl;    -   wherein R¹⁵ is hydrogen, —(C1-C6)alkyl, —CH₂-phenyl, or        —CH₂-(5-to 10-membered)heteroaryl, wherein the —(C1-C6)alkyl,        —CH₂-phenyl, or —CH₂-(5-to 10-membered)heteroaryl are        substituted with 0-3 substituents selected from the group        consisting of —OH, —SH, —SCH₃, —C(O)NH₂, —C(O)OH, —NH₂ and        —NH—C(═NH)NH₂;    -   wherein R¹⁶ is hydrogen or —(C1-C6)alkyl;

-   -   wherein R⁷ is selected from the group consisting of        —(C1-C3)alkyl, —(C3-C6)cycloalkyl, and -(4- to        6-membered)heterocycloalkyl, wherein R⁷ is substituted with 0-3        R″;    -   wherein R⁸ and R⁹ are independently selected from the group        consisting of hydrogen, —(C1-C3)alkyl, —(C3-C6)cycloalkyl, and        -(4- to 6-membered)heterocycloalkyl, wherein R⁸ and R⁹ are        independently substituted with 0-3 R″;    -   wherein R″ is hydrogen, halogen, —(C1-C6)alkyl, —O—(C1-C6)alkyl,        or -(4- to 20-membered)heteroalkyl, wherein said heteroalkyl has        1-6 oxygen atoms;

-   wherein B is a (6- to 8-membered)heterocycloalkyl, wherein B is    substituted with a (C1-C4)alkyl, cyclopropyl, cyclobutyl,    cyclopentyl, cyclohexyl, so as to form a bicyclic ring, and/or    substituted with 0-3 (C1-C4)alkyl, cyclopropyl, cyclobutyl,    cyclopentyl, cyclohexyl, heteroaryl, (C1-C6)aryl, (C5 to    C6)heteroaryl, (C1-C4)acyl, (C1-C4)alkenyl and (C1-C4)alkynyl,    wherein the (C1-C4)alkyl, (C1-C4)alkenyl and (C1-C4)alkynyl are    optionally substituted with 1-3 halogen or (C1-C4)alkoxy;

-   or is selected from Moiety B¹ or Moiety B², wherein Moiety B¹ has    the structure:

-   -   wherein each occurrence of R¹² and R¹³ is independently selected        from the group consisting of hydrogen, —(C1-C10)alkyl,        —(C3-C10)cycloalkyl, -(4- to 10-membered)heteroaryl, and -(4- to        10-membered)heterocycloalkyl, wherein each of R¹² and R¹³ is        independently substituted with 0-3 R′; or    -   wherein two R¹³ groups taken with the nitrogen atoms to which        they are attached combine to form a (7- to        8-membered)heterocycloalkyl, wherein the (7- to        8-membered)heterocycloalkyl is substituted with a (C1-C4)alkyl,        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, so as to form        a bicyclic ring, and/or substituted with 0-3 (C1-C4)alkyl,        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heteroaryl,        (C1-C6)aryl, (C5 to C6)heteroaryl, (C1-C4)acyl, (C1-C4)alkenyl        and (C1-C4)alkynyl,    -   wherein the (C1-C4)alkyl, cyclopropyl, cyclobutyl, cyclopentyl        and cyclohexyl are optionally substituted with 1-3 halogen or        (C1-C4)alkoxy; wherein R′ is selected from hydrogen, halogen,        (C1-C4)alkyl, or —O—(C1-C4)alkyl; and

-   wherein Moiety B² has the structure:

-   wherein n is an integer selected from the group consisting of 1, 2,    3, and 4; and provided that the compound is not

In one or more embodiments of formula I, A is hydrogen. In one or moreembodiments of formula I, A is Moiety A¹. In one or more embodiments offormula I, A is Moiety A². In one or more embodiments of formula I, A isMoiety A³.

In one or more embodiments, the disclosure is directed to a compoundhaving a structure according to formula I, wherein B is a (6- to8-membered)heterocycloalkyl. In one or more embodiments of formula I, Bis a (6- to 8-membered)heterocycloalkyl containing at least two N atoms.In one or more embodiments of formula I, B is a (6- to8-membered)heterocycloalkyl selected from the group consisting of

In one or more embodiments of formula I, B is Moiety B¹. In one or moreembodiments of formula I, B is Moiety B². In one or more embodiments offormula I, B is substituted with a (C1-C4)alkyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, so as to form a bicyclic ring,and/or substituted with 0-3 (C1-C4)alkyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, heteroaryl, (C1-C6)aryl, (C5 to C6)heteroaryl,(C1-C4)acyl, (C1-C4)alkenyl and (C1-C4)alkynyl. In one or moreembodiments of formula I, the (C1-C4)alkyl, (C1-C4)alkenyl and(C1-C4)alkynyl are optionally substituted with 1-3 halogen or(C1-C4)alkoxy. In one or more embodiments of formula I, B is substitutedwith a (C1-C4)alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,so as to form a bicyclic ring, and/or substituted with 0-3 (C1-C4)alkyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heteroaryl,(C1-C6)aryl, (C5 to C6)heteroaryl, (C1-C4)acyl, (C1-C4)alkenyl and(C1-C4)alkynyl, wherein the (C1-C4)alkyl, (C1-C4)alkenyl and(C1-C4)alkynyl are optionally substituted with 1-3 halogen or(C1-C4)alkoxy.

In some embodiments of the disclosure, the compound according to formulaI is a compound having a structure according to formula II:

or a pharmaceutically acceptable salt, solvate, hydrate, or polymorphthereof, or a solvate, hydrate, or polymorph of the pharmaceuticallyacceptable salt, wherein R⁰, R¹, R², R¹² and R¹³ are as defined informula I.

In some embodiments of the compound having a structure according toformula I or II, each of R¹ and R² is independently hydrogen or—(CH(R⁶))—O—C(O)R¹⁰. In one or more embodiments of formula I or II, oneof R¹ and R² is H, and the other is —(CH(R⁶))—O—C(O)R¹⁰. In one or moreembodiments of formula I or II, both R¹ and R² are —(CH(R⁶))—O—C(O)R¹⁰.In one or more embodiments of formula I or II, both R¹ and R² are H.

In some embodiments of formula I or II, each of R¹ and R² isindependently hydrogen, —(CH(R⁶))_(m)—S—C(O)R¹⁰ or—CH₂—(C(R¹¹)₂)—C(O)—CH₂—S—C(O)R¹⁰, m being selected from the integers of1, 2 ,3 or 4. In one or more embodiments of formula I or II, one of R¹and R² is H and the other is —CH₂—(C(R¹¹)₂)—C(O)—CH₂—S—C(O)R¹⁰. In oneor more embodiments of formula I or II, one of R¹ and R² is H, and theother is —(CH(R⁶))_(m)—S—C(O)R¹⁰. In one or more embodiments of formulaI or II, R¹ and R² are (CH(R⁶))_(m)—S—C(O)R¹⁰. In one or moreembodiments of formula I or II, R¹ and R² are—CH₂—(C(R¹¹)₂)—C(O)—CH₂—S—C(O)R¹⁰.

In one or more embodiments of formula I or II, each R⁶ is independentlyhydrogen or (C1-C3)alkyl. In one or more embodiments of formula I or II,each R⁶ is independently hydrogen or (C1-C3)alkyl. In one or moreembodiments of formula I or II, each R⁶ is independently hydrogen,methyl, ethyl, propyl or iso-propyl.

In some embodiments of the compound having a structure according toformula I or II, R¹⁰ is an optionally substituted —(C1-C6)alkyl,—O—(C1-C6)alkyl, —O—(C6-C10)aryl, —(C6-C10)aryl, (5- to10-membered)heteroaryl, (4- to 10-membered)heterocycloalkyl,(C3-C10)cycloalkyl, —O-(5- to 10-membered)heteroaryl, —O-(4- to10-membered)heterocycloalkyl, —O—(C3-C10)cycloalkyl, —O-(4- to20-membered)heteroalkyl or -(4- to 20-membered)heteroalkyl, wherein eachof said heteroalkyl independently has 1-6 oxygen atoms. In one or moreembodiments of the compound having a structure according to formula I orII, R¹⁰ is an optionally substituted —(C1-C6)alkyl, —O—(C1-C6)alkyl,—(C6-C10)aryl, -(4- to 20-membered)heteroalkyl and —O-(4- to20-membered)heteroalkyl, wherein each of said heteroalkyl independentlyhas 1-6 oxygen atoms. In some embodiments, R¹⁰ is an optionallysubstituted —(C1-C6)alkyl, —O—(C1-C6)alkyl, —(C6-C10)aryl,—[(CH₂)_(y)O]_(z)—R, —CH₂—O—[(CH₂)_(y)O]_(z)—R and—O—[(CH₂)_(y)O]_(z)—R, wherein y is an integer between 1 and 4; z is aninteger between 1 and 10; and R is hydrogen or (C1-C6)alkyl. In someembodiments, R¹⁰ is an optionally substituted (C1-C6)alkyl, or(C6-C10)aryl. In some embodiments, R¹⁰ is methyl, ethyl, propyl, butyl,iso-propyl, tent-butyl or phenyl. In some embodiments, R¹⁰ is—[(CH₂)_(y)O]_(z)—R, —CH₂—O—[(CH₂)_(y)O]_(z)—R or —O—[(CH₂)_(y)O]_(z)—R,wherein y is 2; x is an integer selected from the group consisting of 1,2, 3 and 4; and R is —(C1-C6)alkyl. In some embodiments R¹⁰ is—CH₂—O—[(CH₂)₂O]—(C1-C6)alkyl or —O[(CH₂)₂O]4—(C1-C6)alkyl.

In some embodiments, R¹⁰ is unsubstituted. In some embodiments, R¹⁰ issubstituted with 0-3 R^(c), wherein R^(c) is selected from the groupconsisting of halogen (e.g., —F, —Cl, —Br, —I), (C1-C3)alkyl, —CN,—O—(C1-C3)alkyl, —S—(C1-C3)alkyl, and C(O)O—(C1-C3)alkyl. In someembodiments, R^(c) is (C1-C3)alkyl (e.g., methyl, ethyl, propyl,iso-propyl) or —C(O)O—(C1-C3)alkyl (e.g., —C(O)O-methyl, —C(O)O-ethyl,—C(O)O-propyl, —C(O)O-iso-propyl). In some embodiments, R^(c) is(C1-C3)alkyl (e.g., methyl, ethyl, propyl, iso-propyl).

In one or more embodiments of formula I or II, each R¹¹ is independentlyselected from the group consisting of hydrogen, —(C1-C6)alkyl,—CH₂—O—C(O)R″, —C(O)—OR″, -(4- to 20-membered)heteroalkyl and —O-(4- to20-membered)heteroalkyl, wherein each of said heteroalkyl independentlyhas 1-6 oxygen atoms. In some embodiments, each R¹¹ is independentlyselected from the group consisting of hydrogen, —(C1-C6)alkyl,—CH₂—O—C(O)R″, —C(O)—OR″, —[(CH₂)_(y)O]_(z)—R, —CH₂—O—[(CH₂)_(y)O]_(z)—Rand —O—[(CH₂)_(y)O]_(z)—R, wherein y is an integer between 1 and 4; z isan integer between 1 and 10; and R is hydrogen or (C1-C6)alkyl (e.g.,methyl, ethyl, propyl, iso-propyl, butyl, tent-butyl, pentyl, hexyl). Insome embodiments of formula I or II, each R¹¹ is independently hydrogen,—(C1-C6)alkyl, —CH₂—O—C(O)R″ or —C(O)—OR″.

In some embodiments of formula I or II, each R¹¹ is independentlyhydrogen, —(C1-C3)alkyl, —CH₂—O—C(O)R″ and —C(O)—OR″, wherein R″ ishydrogen, (C1-C6)alkyl, or -(4- to 20-membered)heteroalkyl, wherein saidheteroalkyl has 1-6 oxygen atoms. In some embodiments of formula I orII, R″ is hydrogen, (C1-C6)alkyl, or —[(CH₂)_(y)O]_(z)—R, wherein y isan integer between 1 and 4; z is an integer between 1 and 10; and R ishydrogen or (C1-C6)alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl orhexyl). In some embodiments of formula I or II, R″ is methyl, ethyl,propyl, iso-propyl, or [(CH₂)₂O]₃—CH₃.

In one or more embodiments of formula I or II, each R¹¹ of the same R¹or R² group is a —(C1-C6)alkyl (e.g., methyl, ethyl, propyl, butyl,pentyl, hexyl). In some embodiments, one R¹¹ of the same R¹ or R² groupis a —(C1-C6)alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl),and the other is —CH₂—O—C(O)R″ or —C(O)—OR″. In some embodiments, eachR¹¹ of the same R¹ or R² group is independently —CH₂—O—C(O)R″or—C(O)—OR″.

In one or more embodiments of formula I or II, when R¹¹ is —CH₂—O—C(O)R″or —C(O)—OR″, R″ is hydrogen, halogen, —(C1-C6)alkyl, —O—(C2-C6)alkyl,or -(4- to 20-membered)heteroalkyl, wherein said heteroalkyl has 1-6oxygen atoms. In one or more embodiments of formula I or II, when R¹¹ is—CH₂—O—C(O)R″ or —C(O)—OR″, R″ is hydrogen, (C1-C6)alkyl, or -(4- to20-membered)heteroalkyl, wherein said heteroalkyl has 1-6 oxygen atoms.In one or more embodiments of formula I or II, when R¹¹ is —CH₂—O—C(O)R″or —C(O)—OR″, R″ is (C1-C6)alkyl, or -(4- to 20-membered)heteroalkyl,wherein said heteroalkyl has 1-6 oxygen atoms. In one or moreembodiments of formula I or II, when R¹¹ is —CH₂—O—C(O)R″ or —C(O)—OR″,R″ is (C1-C6)alkyl or —[(CH₂)_(y)O]_(z)—R, wherein y is an integerbetween 1 and 4; z is an integer between 1 and 10; and R is hydrogen or(C1-C6)alkyl. In one or more embodiments of formula I or II, when R¹¹ is—CH₂—O—C(O)R″ or —C(O)—OR″, R″ is methyl, ethyl, propyl, iso-propyl,butyl, tent-butyl, pentyl, hexyl or —[(CH₂)₂O]₃—CH₃.

In one or more embodiments of formula I or II, R¹ and R², taken with the—O—P—O-linkage to which they are attached form a 6-memberedheterocycloalkyl ring that is substituted with 1-2 R^(a) and 0-3 R^(b).In one or more embodiments of formula I or II, R¹ and R², one of whichis CH₂ or the other is CH₂CH₂, taken with the —O—P—O-linkage to whichthey are attached form a 6-membered heterocycloalkyl ring that issubstituted with 1-2 R^(a) and 0-3 R^(b). In some embodiments, when R¹and R², taken with the —O—P—O-linkage to which they are attached form a6-membered heterocycloalkyl ring, the heterocycloalkyl ring is1,3,2-dioxaphosphinane. In some embodiments, when R¹ and R², one ofwhich is CH₂ or the other is CH₂CH₂, taken with the —O—P—O-linkage towhich they are attached form a 6-membered heterocycloalkyl ring, theheterocycloalkyl ring is 1,3,2-dioxaphosphinane. In some embodiments,when R¹ and R², taken with the —O—P—O-linkage to which they are attachedform a 6-membered heterocycloalkyl ring, the heterocyclalkyl ring is1,3,2-λ-5 dioxaphosphinane. In some embodiments, when R¹ and R², one ofwhich is CH2 or the other is CH₂CH₂, taken with the —O—P—O-linkage towhich they are attached form a 6-membered heterocycloalkyl ring, theheterocyclalkyl ring is 1,3,2-λ-5 dioxaphosphinane. In some embodiments,R^(a) is independently hydrogen, (C1-C6)alkyl, (C6-C10)aryl- or a 5- to10-membered heteroaryl-, provided that at least one R^(a) group is(C6-C10)aryl- or a 5- to 10-membered heteroaryl-, wherein said alkyl,aryl and heteroaryl R^(a) is substituted with 0-3 R^(c). In someembodiments, R^(a) is R^(a1) or R^(a2), and R^(a1) and R^(a2) areindependently selected from hydrogen, (C1-C6)alkyl, (C6-C10)aryl or a 5-to 10-membered heteroaryl, wherein said alkyl, aryl and heteroaryl aresubstituted with 0-3 R^(c), provided that at least one of R^(a1) andR^(a2) is (C6-C10)aryl or a 5- to 10-membered heteroaryl. In someembodiments, R^(b) is —(C1-C3)alkyl. In some embodiments of formula I orII, R^(b) is R^(d), R^(e1) or R^(e2), and R^(d) is hydrogen or(C1-C3)alkyl; and R^(e1) and R^(e2) are independently hydrogen or(C1-C3)alkyl, provided that when R^(a1) is (C6-C10)aryl or a 5- to10-membered heteroaryl, R^(e1) is hydrogen, and that when R^(a2) is(C6-C10)aryl or a 5- to 10-membered heteroaryl, R^(e2) is hydrogen.

In some embodiments of the disclosure, the compound according to formulaI or II has a structure according to formula III:

-   or a pharmaceutically acceptable salt, solvate, hydrate, or    polymorph thereof, or a solvate, hydrate, or polymorph of the    pharmaceutically acceptable salt, wherein: R⁰, R¹² and R¹³ are as    defined in formula I;-   R^(a1) and R^(a2) are independently selected from hydrogen,    (C1-C6)alkyl, (C6-C10)aryl or a 5- to 10-membered heteroaryl,    wherein said alkyl, aryl and heteroaryl are substituted with 0-3    R^(c), provided that at least one of R^(a1) and R^(a2) is    (C6-C10)aryl or a 5- to 10-membered heteroaryl;-   R^(d) is hydrogen or (C1-C3)alkyl; and-   R^(e1) and R^(e2) are independently hydrogen or (C1-C3)alkyl,    provided that when R^(a1) is (C6-C10)aryl or a 5- to 10-membered    heteroaryl, R^(e1) is hydrogen, and that when R^(a2) is (C6-C10)aryl    or a 5- to 10-membered heteroaryl, R^(e2) is hydrogen.

In one or more embodiments of formula I, II or III, R^(a1) is selectedfrom hydrogen, (C1-C6)alkyl, (C6-C10)aryl or 5- to 10-memberedheteroaryl, and R^(a2) is selected from hydrogen, (C1-C6)alkyl,(C6-C10)aryl or a 5- to 10-membered heteroaryl, wherein said alkyl, aryland heteroaryl are substituted with 0-3 R^(c). In some embodiments,R^(a1) is phenyl or a 5- to 6-membered heteroaryl. In some embodiments,R^(a2) is phenyl or a 5- to 6-membered heteroaryl. In one or moreembodiments, one of R^(a1) and R^(a2) is phenyl and the other ishydrogen. In one or more embodiments, one of R^(a1) and R^(a2) is a 5-to 6-membered heteroaryl and the other is hydrogen. In some embodiments,the 5- to 6-membered heteroaryl is a nitrogen containing heteroaryl(e.g., pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl,imidazolyl, pyrazolyl, triazolyl, oxazolyl, or isoxazolyl). In someembodiments, the 5- to 6-membered heteroaryl is pyridinyl.

In one or more embodiments of formula I, II or III, R^(d) is hydrogen or(C1-C3)alkyl, and R^(e1) and R^(e2) are H. In one or more embodiments offormula I, II or III, R^(d), R^(e1) and R^(e2) are H.

In one or more embodiments of formula I, II or III, R^(c) is halogen or(C1-C3)alkyl. In one or more embodiments of formula I, II or III, R^(c)is chloro, fluoro, bromo, iodo, methyl, ethyl, propyl or iso-propyl. Inone or more embodiments of formula I, II or III, R^(c) is chloro ormethyl.

In one or more embodiments of formula I, the compound has a structureaccording to formula IV:

or a pharmaceutically acceptable salt, solvate, hydrate, or polymorphthereof, or a solvate, hydrate, or polymorph of the pharmaceuticallyacceptable salt, wherein Y, W, R⁰, R³, R⁴, R⁵, R¹², R¹³, R¹⁴, R¹⁵ andR¹⁶ are as defined in formula I.

In some embodiments of formula I or IV, Y and W are CH. In someembodiments of formula I or IV, one of Y is CH and the other is N. Insome embodiments of formula I or IV, Y and W are N.

In one or more embodiments of formula I or IV, R³ is hydrogen, halogen,(C1-C6)alkyl, (C3-C7)cycloalkyl, (5- to 8-membered)heterocycloalkyl,—O—(C1-C6)alkyl, —O—(C3-C7)cycloalkyl, —O-(5- to8-membered)heterocycloalkyl, (C2-C6)alkenyl, —CH₂OH, phenyl, (5- to6-membered)heteroaryl, or (5- to 6-membered)heterocycloalkyl, wherein R³is substituted with 0-3 substituents selected from the group consistingof halogen, oxo, cyano, —(C1-C6)alkyl, —O—(C1-C6)alkyl, and—C(O)O(C1-C3)alkyl. In one or more embodiments of formula I or IV, R³ ishydrogen, halogen, optionally substituted (C1-C6)alkyl, optionallysubstituted (C2-C6)alkenyl, optionally substituted (C3-C7)cycloalkyl, or—CH₂OH. In one or more embodiments of formula I or IV, R³ is hydrogen,halogen, optionally substituted (C1-C6)alkyl or —CH₂OH.

In one or more embodiments of formula I or IV, R⁴ is hydrogen, —CN,(C1-C6)alkyl, —O—(C1-C6)alkyl, —(C2-C6)alkenyl or —CH₂OH. In one or moreembodiments of formula I or IV, R⁴ is hydrogen, methyl, ethyl, propyl,iso-propyl, —CN, —CH₂OH or methoxy.

In one or more embodiments of formula I or IV, R⁵ is hydrogen, halogen,(C1-C6)alkyl or —O—(C1-C6)alkyl. In one or more embodiments of formula Ior IV, R⁵ is hydrogen, fluoro, chloro, bromo, methyl, ethyl, propyl,iso-propyl or methoxy.

In one or more embodiments of formula I or IV, R³, R⁴ and R⁵ are H.

In one or more embodiments of formula I or IV, R¹⁴ is —(C1-C6)alkyl. Inone or more embodiments of formula I or IV, R¹⁴ is —(C1-C3)alkyl. In oneor more embodiments of formula I or IV, R¹⁴ is methyl, ethyl, propyl oriso-propyl.

In one or more embodiments of formula I or IV, R¹⁵ is hydrogen,—(C1-C6)alkyl, —CH₂-phenyl, or —CH₂-(5-to 10-membered)heteroaryl,wherein the —(C1-C6)alkyl, —CH₂-phenyl, or —CH₂-(5-to10-membered)heteroaryl are substituted with 0-3 substituents selectedfrom the group consisting of —OH, —SH, —SCH₃, —C(O)NH₂, —C(O)OH, —NH₂and —NH—C(═NH)NH₂. In one or more embodiments of formula I or IV, R¹⁵ ishydrogen or —(C1-C6)alkyl, wherein the —(C1-C6)alkyl is substituted with0-1 substituents selected from the group consisting of —OH, —SH, —SCH₃,—C(O)NH₂, —C(O)OH, —NH₂ and —NH—C(═NH)NH₂. In one or more embodiments offormula I or IV, R¹⁵ is methyl. In one or more embodiments of formula Ior IV, R¹⁵ is —CH₂-phenyl substituted with 0-1 —OH. In one or moreembodiments of formula I or IV, R¹⁵ is —CH₂-(5-to10-membered)heteroaryl. In one or more embodiments of formula I or IV,R¹⁵ is —CH₂-(5-to 9-membered)heteroaryl wherein the 5- to 9-memberedheteroaryl is imidiazolyl or indolyl.

In one or more embodiments of formula I or IV, R¹⁶ is hydrogen or(C1-C6)alkyl. In one or more embodiments of formula I or IV, R¹⁶ ishydrogen or (C1-C3)alkyl (e.g., methyl, ethyl, propyl and the like).

In some embodiments of formula I, the compound has a structure accordingto formula V:

or a pharmaceutically acceptable salt, solvate, hydrate, or polymorphthereof, or a solvate, hydrate, or polymorph of the pharmaceuticallyacceptable salt, wherein R⁰, R⁷, R⁸, R⁹, R¹² and R¹³ are as defined informula I.

In some embodiments of formula I or V, R⁷ is —(C1-C3)alkyl,—(C3-C6)cycloalkyl, and -(4- to 6-membered)heterocycloalkyl. In someembodiments of formula I or V, R⁷ is —(C1-C3)alkyl or—(C3-C6)cycloalkyl. In some embodiments of formula I or V, R⁷ is(C1-C3)alkyl. In some embodiments of formula I or V, R⁷ is methyl, ethylor propyl.

In one or more embodiments of formula I or V, R⁸ and R⁹ areindependently selected from the group consisting of hydrogen,—(C1-C3)alkyl, —(C3-C6)cycloalkyl, and -(4- to6-membered)heterocycloalkyl. In one or more embodiments of formula I orV, R⁸ and R⁹ are independently selected from the group consisting ofhydrogen, —(C1-C3)alkyl or —(C3-C6)cycloalkyl. In one or moreembodiments of formula I or V, R⁸ and R⁹ are independently selected fromthe group consisting of hydrogen or —(C1-C3)alkyl. In one or moreembodiments of formula I or V, R⁸ and R⁹ are independently selected fromthe group consisting of hydrogen, methyl, ethyl or propyl.

In one or more embodiments of formula I or V, R⁷, R⁸ and R⁹ aresubstituted with 0-3 R″, wherein R″ is halogen, —(C1-C6)alkyl or—O—(C1-C6)alkyl. In one or more embodiments of formula I or V, R⁷, R⁸and R⁹ are unsubstituted.

In some embodiments of formula I, the compound has a structure accordingto formula VI:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,prodrug or double prodrug thereof, or a solvate, hydrate, or polymorphof the pharmaceutically acceptable salt, wherein R⁰, R¹² and R¹³ are asdefined in formula I, provided that the compound is not

In one or more embodiments of formula I or VI, R⁰ is independentlyhydrogen or (C1-C3)alkyl. In one or more embodiments of formula I or VI,one R⁰ is hydrogen and the other is (C1-C3)alkyl. In one or moreembodiments of formula I or VI, R⁰ is independently hydrogen,(C1-C3)alkyl, or a thiol. In one or more embodiments of formula I or VI,one R⁰ is hydrogen and the other is a thiol. In one or more embodimentsof formula I or VI, each R⁰ are (C1-C3)alkyl (e.g., methyl, ethyl,propyl, or iso-propyl). In some embodiments, each R⁰ is methyl.

In some embodiments of formula I or VI, each R¹² is independentlyhydrogen or (C1-C3)alkyl. In some embodiments of formula I or VI, eachR¹² is hydrogen.

In some embodiments of formula I or VI, each R¹³ is taken together withthe nitrogen atoms to which they are attached to form a (7- to8-membered)heterocycloalkyl. In some embodiments, each R¹³ is takentogether with the nitrogen atoms to which they are attached to form

In some embodiments of formula I, the compound has a structure accordingto formula VII,

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,prodrug or double prodrug thereof, or a solvate, hydrate, or polymorphof the pharmaceutically acceptable salt, wherein R⁰ and B are as definedin formula I, provided that the compound is not

In one or more embodiments of formula I or VII, R⁰ is independentlyhydrogen or (C1-C3)alkyl. In one or more embodiments of formula I orVII, one R⁰ is hydrogen and the other is (C1-C3)alkyl. In one or moreembodiments of formula I or VII, R⁰ is independently hydrogen,(C1-C3)alkyl or a thiol. In one or more embodiments of formula I or VII,one R⁰ is hydrogen and the other is a thiol. In one or more embodimentsof formula I or VII, each R⁰ are (C1-C3)alkyl (e.g., methyl, ethyl,propyl, iso-propyl). In some embodiments, each R⁰ is methyl.

In one or more embodiments of formula I or VII, B is a (6- to8-membered) heterocycloalkyl or Moiety B¹, wherein B is substituted with0-3 (C1-C4)alkyl or cyclopropyl, wherein the (C1-C4)alkyl andcyclopropyl are optionally substituted with 1-3 halogen or(C1-C4)alkoxy. In one or more embodiments of formula I or VII, B is a(6- to 8-membered) heterocycloalkyl or Moiety B¹, wherein B issubstituted with a (C1-C4)alkyl, cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl, so as to form a bicyclic ring, and/or substituted with 0-3(C1-C4)alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,heteroaryl, (C1-C6)aryl, (C5 to C6)heteroaryl, (C1-C4)acyl,(C1-C4)alkenyl and (C1-C4)alkynyl, wherein the (C1-C4)alkyl,(C1-C4)alkenyl and (C1-C4)alkynyl are optionally substituted with 1-3halogen or (C1-C4)alkoxy. In one or more embodiments of formula I orVII, B is a (6- to 8-membered) heterocycloalkyl, Moiety B¹ or Moiety B²,wherein B is substituted with a (C1-C4)alkyl, cyclopropyl, cyclobutyl,cyclopentyl cyclohexyl, so as to form a bicyclic ring, and/orsubstituted with 0-3 (C1-C4)alkyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, heteroaryl, (C1-C6)aryl, (C5 to C6)heteroaryl, (C1-C4)acyl,(C1-C4)alkenyl and (C1-C4)alkynyl, wherein the (C1-C4)alkyl,(C1-C4)alkenyl and (C1-C4)alkynyl are optionally substituted with 1-3halogen or (C1-C4)alkoxy. In one or more embodiments of formula I orVII, B is Moiety B¹, wherein two R13 groups taken with the nitrogenatoms to which they are attached combine to form a (7- to8-membered)heterocycloalkyl, wherein the (7- to8-membered)heterocycloalkyl is substituted with a (C1-C4)alkyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, so as to form abicyclic ring, and/or substituted with 0-3 (C1-C4)alkyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, heteroaryl, (C1-C6)aryl, (C5 toC6)heteroaryl, (C1-C4)acyl, (C1-C4)alkenyl and (C1-C4)alkynyl, whereinthe (C1-C4)alkyl, (C1-C4)alkenyl and (C1-C4)alkynyl are optionallysubstituted with 1-3 halogen or (C1-C4)alkoxy. In some embodiments offormula I or VII, B is a (6- to 8-membered) heterocycloalkyl containingat least two N atoms. In some embodiments, B is selected from the groupconsisting of

In some embodiments, B is

In some embodiments of formula I or VII, B is Moiety B¹, and each R¹²and R¹³ is independently hydrogen or —(C1-C6)alkyl. In some embodimentsof formula I or VII, B is Moiety B², and each R¹² and R¹³ isindependently hydrogen or —(C1-C6)alkyl. In some embodiments each R¹² ishydrogen, and each R¹³ is —(C1-C6)alkyl. In some embodiments of formulaI or VII, each R¹² is hydrogen, and each R¹³ is methyl, provided that R⁰is not hydrogen. In some embodiments of formula I or VII, R¹² isindependently hydrogen or -(4- to 10-membered)heteroaryl. In someembodiments of formula I or VII, R¹² is independently hydrogen orpyridine.

In one or more embodiments of formula I, II, III, IV, V, VI or VII, R⁰is independently hydrogen or (C1-C3)alkyl. In one or more embodiments offormula I, II, III, IV, V, VI or VII, one R⁰ is hydrogen and the otheris (C1-C3)alkyl. In one or more embodiments of formula I, II, III, IV,V, VI or VII, R⁰ is independently hydrogen, (C1-C3)alkyl, or a thiol. Inone or more embodiments of formula I, II, III, IV, V, VI or VII, one R⁰is hydrogen and the other is a thiol. In one or more embodiments offormula I, II, III, IV, V, VI or VII, each R⁰ are (C1-C3)alkyl (e.g.,methyl, ethyl, propyl, or iso-propyl). In some embodiments, each R⁰ ismethyl.

In one or more embodiments of formula I, II, III, IV, V, VI or VII, eachR¹² is independently selected from the group consisting of hydrogen,—(C1-C10)alkyl, —(C3-C10)cycloalkyl, and -(4- to10-membered)heterocycloalkyl, wherein each R¹² is independentlysubstituted with 0-3 R′. In one or more embodiments of formula I, II,III, IV, V, VI or VII, each R¹² is independently selected from the groupconsisting of hydrogen, —(C1-C10)alkyl, —(C3-C10)cycloalkyl, -(4- to10-membered)heteroaryl, and -(4- to 10-membered)heterocycloalkyl,wherein each R¹² is independently substituted with 0-3 R′. In one ormore embodiments of formula I, II, III, IV, V, VI or VII, each R¹² isindependently hydrogen or —(C1-C10)alkyl. In one or more embodiments offormula I, II, III, IV, V, VI or VII, each R¹² is independently hydrogenor -(4- to 10-membered)heteroaryl. In one or more embodiments of formulaI, II, III, IV, V, VI or VII, each R¹² is independently hydrogen orpyridine. In one or more embodiments of formula I, II, III, IV, V, VI orVII, each R¹² is independently hydrogen, methyl, ethyl, propyl,iso-propyl, butyl, tert-butyl, pentyl, neopentyl, hexyl, heptyl, octyl,nonyl or decyl. In one or more embodiments of formula I, II, III, IV, V,VI or VII, each R¹² is hydrogen or methyl.

In one or more embodiments of formula I, II, III, IV, V, VI or VII, eachR¹³ is independently selected from the group consisting of hydrogen,—(C1-C10)alkyl, —(C3-C10)cycloalkyl, and -(4- to10-membered)heterocycloalkyl, wherein each R¹³ is independentlysubstituted with 0-3 R′. In one or more embodiments of formula I, II,III, IV, V, VI or VII, each R¹³ is independently hydrogen or—(C1-C10)alkyl. In one or more embodiments of formula I, II, III, IV, V,VI or VII, each R¹³ is independently hydrogen, methyl, ethyl, propyl,iso-propyl, butyl, tent-butyl, pentyl, neopentyl, hexyl, heptyl, octyl,nonyl or decyl. In one or more embodiments of formula I, II, III, IV, V,VI or VII, each R¹³ is hydrogen or methyl.

In some embodiments of formula I, II, III, IV, V, VI or VII, each R¹³ istaken together with the nitrogen atoms to which they are attached toform a (7- to 8-membered) heterocycloalkyl. In some embodiments, eachR¹³ is taken together with the nitrogen atoms to which they are attachedto form

In some embodiments, the disclosure is directed to a compound having astructure according to formula II:

-   or a pharmaceutically acceptable salt, solvate, hydrate, or    polymorph thereof, or a solvate, hydrate, or polymorph of the    pharmaceutically acceptable salt, wherein:-   each R⁰ is hydrogen;-   each of R¹ and R² is independently hydrogen or —(CH(R⁶))—O—C(O)R¹⁰;-   each R⁶ is independently hydrogen or (C1-C3)alkyl;-   each R¹⁰ is independently selected from the group consisting of    —(C1-C6)alkyl, —O—(C1-C6)alkyl, —(C6-C10)aryl, -(4- to    20-membered)heteroalkyl, —O-(4- to 20-membered)heteroalkyl,    —[(CH₂)_(y)O]_(z)—R, —CH₂—O—[(CH₂)_(y)O]_(z)—R and    —O—[(CH₂)_(y)O]_(z)—R, wherein each of said heteroalkyl    independently has 1-6 oxygen atoms, wherein y is an integer between    1 and 4, wherein z is an integer between 1 and 10, wherein R is    hydrogen or (C1-C6)alkyl, and wherein each R¹⁰ is independently    substituted with 0-3 R^(c) groups;-   R^(c) is selected from the group consisting of halogen,    (C1-C3)alkyl, —CN, —O—(C1-C3)alkyl, —S—(C1-C3)alkyl, and    —O—C(O)(C1-C3)alkyl;-   each R¹² is hydrogen; and-   each R¹³ is (C1-C3)alkyl.

In some embodiments, the disclosure is directed to a compound having astructure according to formula II, or a pharmaceutically acceptablesalt, solvate, hydrate, or polymorph thereof, or a solvate, hydrate, orpolymorph of the pharmaceutically acceptable salt, wherein: each R⁰ ishydrogen;

-   each of R¹ and R² is independently hydrogen, —(CH(R⁶))_(m)—S—C(O)R¹⁰    or —CH₂—(C(R¹¹)₂)—C(O)—CH₂—S—C(O)R¹⁰,-   each R¹² is hydrogen;-   each R¹³ is a (C1-C3)alkyl;-   each R⁶ is hydrogen;-   R¹⁰ is selected from the group consisting of (C1-C6)alkyl, and    (C6-C10)aryl, wherein each R¹⁰ is substituted with 0-3 R^(c);-   each R¹¹ is independently selected from the group consisting of    hydrogen, —(C1-C3)alkyl, —CH₂—O—C(O)R″ and —C(O)—OR″;-   each R^(c) is (C1-C3)alkyl or —C(O)O—(C1-C3)alkyl;-   R″ is hydrogen, (C1-C6)alkyl, or -(4- to 20-membered)heteroalkyl,    wherein said heteroalkyl has 1-6 oxygen atoms; and-   m is an integer selected from the group consisting of 0, 1, 2, 3 and    4.

In one or more embodiments, the disclosure is directed to a compoundhaving a structure according to formula III,

-   or a pharmaceutically acceptable salt, solvate, hydrate, or    polymorph thereof, or a solvate, hydrate, or polymorph of the    pharmaceutically acceptable salt, wherein:-   each R⁰ is independently hydrogen;-   each R¹² and R¹³ is independently selected from the group consisting    of hydrogen, —(C1-C3)alkyl, —(C3-C6)cycloalkyl, and -(4- to    6-membered)heterocycloalkyl, wherein each of R³ and R⁴ is    independently substituted with 0-3 R′;-   R^(a1) and R^(a2) is independently hydrogen, (C1-C6)alkyl,    (C6-C10)aryl or a 5- to 10-membered heteroaryl, wherein said alkyl,    aryl and heteroaryl are substituted with 0-3 R^(c), provided that at    least one of R^(a1) and R^(a2) is (C6-C10)aryl or a 5- to    10-membered heteroaryl;-   R^(c) is selected from the group consisting of hydrogen, halogen,    (C1-C3)alkyl, —CN, —O—(C1-C3)alkyl, —S—(C1-C3)alkyl,    —C(O)O—(C1-C3)alkyl, —N(R′)₂, —CF₃ and —OCF₃;-   R^(d) is hydrogen or (C1-C3)alkyl;-   R^(e1) and R^(e2) are independently hydrogen or (C1-C3)alkyl,    provided that when R^(a1) is (C6-C10)aryl or a 5- to 10-membered    heteroaryl, R^(e1) is hydrogen, and that when R^(a2) is (C6-C10)aryl    or a 5- to 10-membered heteroaryl, R^(e2) is hydrogen; and-   R′ is hydrogen or —(C1-C4)alkyl.

In some embodiments, the disclosure is directed to a compound having astructure according to formula III, or a pharmaceutically acceptablesalt, solvate, hydrate, or polymorph thereof, or a solvate, hydrate, orpolymorph of the pharmaceutically acceptable salt, wherein:

-   each R⁰ is hydrogen;-   each R¹² is hydrogen;-   each R¹³ is (C1-C3)alkyl;-   one of R^(a1) and r^(a2) is (C6-C10)aryl or a 5- to 10-membered    heteroaryl, and the other is hydrogen, wherein said aryl or    heteroaryl is substituted with 1-3 R^(c);-   each R^(c) is halogen or (C1-C3)alkyl; and-   each of R^(d), R^(e1) and R^(e2) is hydrogen.

In some embodiments, the disclosure is directed to a compound having astructure according to formula IV:

-   or a pharmaceutically acceptable salt, solvate, hydrate, or    polymorph thereof, or a solvate, hydrate, or polymorph of the    pharmaceutically acceptable salt, wherein:-   each R⁰ is independently hydrogen or (C1-C3)alkyl;-   each R¹² and R¹³ is independently selected from the group consisting    of hydrogen, —(C1-C4)alkyl, —(C3-C6)cycloalkyl, and -(4- to    6-membered)heterocycloalkyl, wherein each R¹² and R¹³ is    independently substituted with 0-3 R′;-   R³ is hydrogen, halogen, (C1-C6)alkyl, (C3-C7)cycloalkyl, (5- to    8-membered)heterocycloalkyl, —O—(C1-C6)alkyl, —O—(C3-C7)cycloalkyl,    —O-(5- to 8-membered)heterocycloalkyl, (C2-C6)alkenyl, —CH₂OH,    phenyl, (5- or 6-membered)heteroaryl, or (5- or    6-membered)heterocycloalkyl, wherein R³ is substituted with 0-3    substituents selected from the group consisting of halogen, oxo,    —(C1-05)alkyl, —O—(C2-C4)alkyl, and —C(O)O(C1-C3)alkyl;-   R⁴ is hydrogen, —CN, (C1-C6)alkyl, —O—(C1-C6)alkyl, (C2-C6)alkenyl    or —CH₂OH; or-   R⁴ and R³ are taken together with the carbon atoms to which they are    attached to form a (C5-C6)cycloalkyl, (C6-C10)aryl, (5- to    10-membered)heterocycloalkyl or (5- to 10-membered)heteroaryl;-   R⁵ is hydrogen, halogen, (C1-C6)alkyl or —O—(C1-C6)alkyl; or-   R⁵ and R⁴ are taken together with the carbon atoms to which they are    attached to form a (C5-C6)cycloalkyl, phenyl, (5- or    6-membered)heterocycloalkyl, or (5- or 6-membered)heteroaryl;-   each R⁶ is independently selected from hydrogen or (C1-C3)alkyl;-   R¹⁴ is (C1-C6)alkyl;-   R¹⁵ is hydrogen, —(C1-C6)alkyl, —CH₂-phenyl, or —CH2-(5-to    10-membered)heteroaryl, wherein the —(C1-C6)alkyl, —CH2-phenyl, or    —CH2-(5-to 10-membered)heteroaryl are substituted with 0-3    substituents selected from the group consisting of —OH, —SH, —SCH₃,    —C(O)NH₂, —C(O)OH, —NH₂ and —NH—C(═NH)NH₂;-   R¹⁶ is hydrogen or —(C1-C6)alkyl; and-   R′ is selected from halogen, (C1-C4)alkyl, or —O—(C1-C4)alkyl.

In some embodiments, the disclosure is directed to a compound having astructure according to formula IV, or a pharmaceutically acceptablesalt, solvate, hydrate, or polymorph thereof, or a solvate, hydrate, orpolymorph of the pharmaceutically acceptable salt, wherein:

-   each R⁰ is hydrogen;-   each R¹² is H;-   each R¹³ is independently hydrogen or —(C1-C6)alkyl;-   each R⁶ is independently selected from hydrogen or (C1-C3)alkyl;-   R³, R⁴ and R⁵ are H;-   R¹⁴ is (C1-C3)alkyl;-   R¹⁵ is (C1-C3)alkyl; and-   R16 is H.

In another embodiment, the disclosure is directed to a compound having astructure according to formula V:

-   or a pharmaceutically acceptable salt, solvate, hydrate, or    polymorph thereof, or a solvate, hydrate, or polymorph of the    pharmaceutically acceptable salt, wherein:-   each R⁰ is independently hydrogen or (C1-C3)alkyl-   each R¹² and R¹³ is independently selected from the group consisting    of hydrogen, —(C1-C3)alkyl, —(C3-C10)cycloalkyl, and -(4- to    10-membered)heterocycloalkyl, wherein each R¹² and R¹³ is    independently substituted with 0-3 R′;-   R⁷ is selected from the group consisting of —(C1-C3)alkyl,    —(C3-C6)cycloalkyl, and -(4- to 6-membered)heterocycloalkyl, wherein    R⁷ is substituted with 0-3 R″;-   R⁸ and R⁹ are independently selected from the group consisting of    hydrogen, —(C1-C3)alkyl, —(C3-C6)cycloalkyl, and -(4- to    6-membered)heterocycloalkyl, wherein R⁸ and R⁹ are independently    substituted with 0-3 R″;-   R′ is halogen, (C1-C4)alkyl, or —O—(C1-C4)alkyl; and-   R″ is halogen, —(C1-C6)alkyl or —O—(C2-C6)alkyl.

In some embodiments, the disclosure is directed to a compound having astructure according to formula VI, or a pharmaceutically acceptablesalt, solvate, hydrate, or polymorph thereof, or a solvate, hydrate, orpolymorph of the pharmaceutically acceptable salt, wherein:

-   each R⁰ is hydrogen;-   each R¹² is H;-   each R¹³ is independently —(C1-C3)alkyl; and-   R⁷, R⁸ and R⁹ are —(C1-C3)alkyl.

In another embodiment, the disclosure is directed to a compound having astructure according to formula VI:

-   or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,    prodrug or double prodrug thereof, or a solvate, hydrate, or    polymorph of the pharmaceutically acceptable salt, wherein:-   each R⁰ is independently hydrogen, (C1-C3)alkyl, or —SH;-   each R¹² is independently hydrogen, (C1-C3)alkyl or -(4- to    10-membered)heteroaryl;-   each R¹³ is taken together with the nitrogen atoms to which they are    attached to form a (7- to 8-membered)heterocycloalkyl.

In another embodiment, the disclosure is directed to a compound having astructure according to formula VII:

-   or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,    prodrug or double prodrug thereof, or a solvate, hydrate, or    polymorph of the pharmaceutically acceptable salt, wherein:-   each R⁰ is independently hydrogen, (C1-C3)alkyl or —SH;-   B is a (6- to 8-membered)heterocycloalkyl containing two N atoms,    Moiety B¹, or Moiety B², wherein B is substituted with a    (C1-C4)alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, so    as to form a bicyclic ring, and/or substituted with 0-3    (C1-C4)alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,    heteroaryl, (C1-C6)aryl, (C5 to C6)heteroaryl, (C1-C4)acyl,    (C1-C4)alkenyl and (C1-C4)alkynyl, wherein the (C1-C4)alkyl,    (C1-C4)alkenyl and (C1-C4)alkynyl are optionally substituted with    1-3 halogen or (C1-C4)alkoxy;-   when present, each occurrence of R¹² and R¹³ is independently    hydrogen, —(C1-C6)alkyl, or -(4- to 10-membered)heteroaryl provided    that the compound is not

In some embodiments, the disclosure is directed to a compound having astructure according to formula VII, or a pharmaceutically acceptablesalt, solvate, hydrate, polymorph, prodrug or double prodrug thereof, ora solvate, hydrate, or polymorph of the pharmaceutically acceptablesalt, wherein: wherein B is the heterocycle

wherein the heterocycle is substituted with a (C1-C4)alkyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, so as to form a bicyclic ring,and/or substituted with 0-3 (C1-C4)alkyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, heteroaryl, (C1-C6)aryl, (C5 to C6)heteroaryl,(C1-C4)acyl, (C1-C4)alkenyl and (C1-C4)alkynyl, wherein the(C1-C4)alkyl, (C1-C4)alkenyl and (C1-C4)alkynyl are optionallysubstituted with 1-3 halogen or (C1-C4)alkoxy.

In some embodiments, the compound of this disclosure is selected fromthe group consisting of:

Compound Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

18-(S,S)

18-(R,S)

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph orcombination thereof or a solvate, hydrate or polymorph of the salt.

In some embodiments, the compounds of the disclosure are crystallinesalts. The salt forms of the compounds of the disclosure will havelonger shelf lives compared to the free base form. Without wishing to bebound by theory, the salt forms of the compounds of the disclosure willbe more stable to oxidation and other degradation processes, such asrearrangements, that occur after prolonged storage under ambientconditions.

In some embodiments, the compounds of the disclosure are crystallinesalts derived from inorganic bases, include by way of example only,sodium, potassium, lithium, ammonium, calcium and magnesium salts.

In some embodiments, the compounds of the disclosure are crystallinesalts derived from organic bases including, but not limited to,crystalline salts of primary, secondary and tertiary amines, such asalkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines,di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenylamines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines,di(substituted alkenyl) amines, tri(substituted alkenyl) amines,cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines,substituted cycloalkyl amines, disubstituted cycloalkyl amine,trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl)amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines,disubstituted cycloalkenyl amines, trisubstituted cycloalkenyl amines,aryl amines, diaryl amines, triaryl amines, heterocyclic amines,diheterocyclic amines, triheterocyclic amines, and mixed di- andtri-amines where at least two of the substituents on the amine aredifferent and are selected from the group consisting of alkyl,substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heterocyclic,and the like. In certain such embodiments, also included are amineswhere the two or three substituents, together with the amino nitrogen,form a heterocyclic group. In certain such embodiments, suitable aminesinclude, by way of example only, isopropylamine, trimethyl amine,diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine,2-dimethyl aminoethanol, tromethamine, lysine, arginine, histidine,caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine,glucosamine, N-alkylglucamines, theobromine, purines, piperazine,piperidine, morpholine, N-ethylpiperidine, and the like.

In some embodiments, the compounds of the disclosure arepharmaceutically acceptable crystalline acid addition salts preparedfrom inorganic and organic acids. In certain such embodiments, inorganicacids that can be used to form acid-addition salt forms include, but arenot limited to, hydrochloric acid, hydrobromic acid, sulfuric acid,nitric acid, phosphoric acid, and the like. In some embodiments,crystalline salts derived from organic acids include, but are notlimited to, acetic acid, trifluoroacetic acid, sulfamic acid, propionicacid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonicacid, mucic acid, succinic acid, maleic acid, fumaric acid, tartaricacid, citric acid, benzoic acid, ascorbic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,benzenesulfonic acid, cyclohexylsulfamic acid, 1,5-naphthalenedisulfonicacid, salicylic acid, and the like. In some embodiments, the crystallinesalt is a hydrochloride salt, benzenesulfonate salt, a4-toluenesulfonate salt, a cyclohexylsulfamate salt, a fumarate salt, ahydrobromide salt, a maleate salt, a malonate salt, an oxalate salt, asuccinate salt, a trifluoroacetate salt, a sulfamate salt, an acetatesalt, an ascorbate salt, a mucate salt, a sulfate salt or a1,5-naphthalenedisulfonate salt. In some embodiments, the crystallinesalt is a hydrochloride salt. In some embodiments, the crystalline saltis a benzenesulfonate salt (a besylate salt). In some embodiments, thecrystalline salt is a cyclohexylsulfamate salt. In some embodiments, thecrystalline salt is a fumarate salt. In some embodiments, thecrystalline salt is a hydrobromide salt. In some embodiments, thecrystalline salt is a maleate salt. In some embodiments, the crystallinesalt is a malonate salt. In some embodiments, the crystalline salt is anoxalate salt. In some embodiments, the crystalline salt is a succinatesalt. In some embodiments, the crystalline salt is a trifluoroacetatesalt. In some embodiments, the crystalline salt is a sulfamate salt. Insome embodiments, the crystalline salt is an acetate salt. In someembodiments, the crystalline salt is an ascorbate salt. In someembodiments, the crystalline salt is a mucate salt. In some embodiments,the crystalline salt is a sulfate salt. In some embodiments, thecrystalline salt is a 1,5-naphthalenedisulfonate salt.

In some embodiments, the compounds of this disclosure can exist asvarious solvates, such as with water (also known as hydrates), methanol,ethanol, dimethylformamide, diethyl ether, acetamide, and the like.Mixtures of such solvates can also be prepared. The source of suchsolvates can be from the solvent of crystallization, inherent in thesolvent of preparation or crystallization, or adventitious to suchsolvent. Hydrates may be formed, for example, by combining the3-[3-(methylamino)propylamino]propyl sulfanylphosphonic acid and/or3-[(3-(methylamino) propyl)amino]propane-1-thiol crystalline salts orpolymorphs with water. Hydrates may include monohydrates, dehydrates,trihydrates, tetrahydrates, and so on.

In some embodiments, one or more crystalline salt forms of thedisclosure are thermally stable at about 4° C. for at least two years.In some embodiments, one or more crystalline salt forms of thedisclosure are thermally stable at about ambient temperature for atleast two years. In some embodiments, the one or more crystalline saltforms of the disclosure are thermally stable at about 37° C. for atleast two years. In some embodiments, the crystalline salt forms of thedisclosure are stable at ambient temperature for at least 1 year, 2years, 3 years, 4 years, 5 years, 6 years, 7 years, 7 years, 8 years, 9years or 10 years.

In some embodiments, the compounds and salts of this disclosure canexist as various polymorphs, pseudopolymorphs, or in amorphous state.The term “polymorph” refers to different crystalline forms of the samecompound and other solid-state molecular forms includingpseudo-polymorphs, such as hydrates, solvates, or salts of the samecompound. Different crystalline polymorphs have different crystalstructures due to a different packing of molecules in the lattice, as aresult of changes in temperature, pressure, or variations in thecrystallization process. Polymorphs differ from each other in theirphysical properties, such as X-ray diffraction characteristics,stability, melting points, solubility, or rates of dissolution incertain solvents. Thus, crystalline polymorphic forms are importantaspects in the development of suitable dosage forms in pharmaceuticalindustry.

The disclosure also contemplates all the isomers of the compounds offormulae I, II, III, IV, V, VI and VII. “Isomer” as used herein includesoptical isomers (such as stereoisomers, e.g., diastereomers andenantiomers). Many of the compounds useful in the methods andcompositions of this disclosure have at least one stereogenic center intheir structure. The stereogenic center may be present in an R or Sconfiguration. R and S notation is used in correspondence with the rulesdescribed in Pure Appl Chem. (1976), 45, 11-30. The compounds and saltsof this disclosure can also be in racemic mixtures.

Any embodiment described herein is also intended to represent unlabeledforms as well as isotopically labeled (or isotope containing) forms ofthe compound unless otherwise indicated. Isotopically labeled orcontaining compounds have structures depicted by the formulas givenherein except that one or more atoms are replaced by an atom having aselected atomic mass or mass number. Examples of isotopes that can beincorporated into the compounds of the disclosure include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F, ³¹P, ³²P, ³⁵S, ³⁶Cl, ¹²⁵I,respectively. The invention includes various isotopically labeled orcontaining compounds as defined herein, for example those into whichradioactive isotopes, such as ³H, ¹³C and ¹⁴C are present. Suchisotopically labeled compounds are useful in metabolic studies, reactionkinetic studies, detection or imaging techniques. Isotopically labeledor containing compounds with relatively stable isotopes, for example,²H, may also have enhanced stability as compared to their unlabeledcounterparts, and therefore, may have longer shelf lives and/or longerhalf-lives.

Bioconversion of Prodrugs and Double Prodrugs

Some of the compounds and salts of this disclosure are prodrugs anddouble prodrugs of3-(methylamino)-2-((methylamino)methyl)propane-1-thiol (PrC-210), orderivatives or analogues thereof. A prodrug is administered to a subjectin its inactive form, which is subsequently metabolized in the body intoits active form. For example,{[3-(methylamino)-2-[(methylamino)methyl]propyl]sulfanyl}phosphonic acid(PrC-210-PT) is a prodrug of PrC-210. The PrC-210-PT prodrug isdephosphorylated by alkaline phosphatase into the corresponding thiol(PrC-210), which is the active form of the compound. Due to the polarityof PrC-210-PT, double prodrugs may also be used to enhance thebioavailability of PrC-210 and derivatives or analogues thereof.Accordingly, in some embodiments the double prodrugs of this disclosureare characterized by lipophilic functional groups that aid in enhancingthe absorption of the compounds into the bloodstream, thereby enhancingthe bioavailability of PrC-210. A double prodrug is administered in itsinactive form and is converted to its active form after beingmetabolized by two separate metabolic pathways. The double prodrugs ofthis disclosure, for example, PrC-210-PT-BzOM, are metabolized viavarious enzymes into {[3-(methylamino)-2-[(methylamino)methyl]propyl]sulfanyl}phosphonic acid (PrC-210-PT), or derivatives or analoguesthereof. As described above, the PrC-210-PT prodrug is subsequentlydephosphorylated by alkaline phosphatase into the corresponding thiol(PrC-210). The double prodrugs of this disclosure are derivatives oranalogues of the phosphorothioate compound, PrC-210-PT.

As an example, a bioconversion of the double prodrug compound 2({[(benzoyloxy)methoxy]({[3-(methylamino)-2-[(methylamino)methyl]propyl]sulfanyl})phosphoryl}oxy)methyl benzoate (PrC-210-PT-BzOM) is illustrated inScheme 1. Specifically, serum esterase converts PrC-210-BzOM to thecorresponding phosphorothioate compound (PrC-210-PT), which undergoesdephosphorylation in the presence of alkaline phosphatase, resulting inthe active thiol, PrC-210. This mechanism of double prodrug activationalso applies generically to PrC-210-PT-POE (compound 3), PrC-210-PT-POCE(compound 5), PrC-210-PT-POC (compound 6), PrC-210-PT-PEGOE1 (compound14), PrC-210-PT-PEGOE2 (compound 15) and PrC-210-PT-PEGOE3 (compound16).

As another example, a bioconversion of the compound 7(PrC-210-PT-ClDOxP) is illustrated in Scheme 2. In particular,PrC-210-PT-ClDOxP is converted to the corresponding phosphorothioatederivative in the liver by cytochrome P450 3A4 (CYP3A4). Subsequentdephosphorylation by alkaline phosphatase results in the activecompound, PrC-210. This mechanism of double prodrug activation alsogenerically applies to PrC-210-PT-PyDOxP (compound 8).

As an additional example, a bioconversion of double prodrugPrC-210-PT-PivTB (compound 4) into PrC-210 is illustrated in Scheme 3.PrC-210-PT-PivTB is hydrolyzed to the corresponding thiol by plasmaesterase. A spontaneous base catalyzed reaction subsequently coverts thethiol into the phosphorothioate derivative (PrC-210-PT).Dephosphoylation by alkaline phosphatase furnished the active thiol(PrC-210). This mechanism of double prodrug activation also appliesgenerically to PrC-210-PT-PivTB2 (compound 9), PrC-210-PT-PivTB3(compound 10), PrC-210-PT-PivTB4 (compound 11), and PrC-210-PT-PivTP(compound 12), PrC-210-PT-PEGOE4 (compound 17) and PrC-210-PT-BzTB1(compound 20).

A bioconversion of double prodrug PrC-210-PT-alaf (compound 18) intoPrC-210 is illustrated in Scheme 4 (see, for example, Birkus, G. et al.,Antimicrobial Agents and Chemotherapy, 2016, Vol. 60, pp 316-322).Carboxylesterase 1 (Cesl) cleaves the aryl phosphoester affording thecorresponding hydroxide. Subsequently, lysosomes hydrolyze the P—N bondaffording PrC-210-PT. Dephosphorylation by alkaline phosphatasefurnished the active thiol (PrC-210).

This disclosure also contemplates S-acylated prodrugs of PrC-210 (see,for example, compound 19). S-acylated prodrugs of PrC-210 are morelipophilic than PrC-210, and will exhibit improved bioavailability ascompared to PrC-210. Specifically, after oral administration, lipophilicprodrugs of PrC-210 are expected to pass the gut lumen through passivediffusion more readily than the active thiol. These lipophilic prodrugsmay also pass the blood brain barrier more readily than PrC-210. TheS-acyl prodrugs of this disclosure are believed to be metabolized intothe active thiol form, PrC-210, by esterases or lipases in the plasmaand cerebrospinal fluid.

Pharmaceutical Compositions

In some embodiments, one or more compounds and salts of the disclosureare useful in the preparation of pharmaceutical compositions.Pharmaceutical compositions in accordance with this disclosure may beformulated in a conventional manner using one or more physiologicallyacceptable carriers comprising excipients and auxiliaries whichfacilitate processing of one or more compounds and salts of thedisclosure into compositions which can be used pharmaceutically.Formulation is dependent upon the route of administration chosen.

In some embodiments, the pharmaceutical compositions of the disclosureare for oral administration. In certain such embodiments, one or morecompounds and salts of the disclosure can be formulated readily bycombining the compounds with pharmaceutically acceptable carriers wellknown in the art. Such carriers enable one or more compounds or salts ofthe disclosure to be formulated as tablets, pills, dragees, capsules,liquids, gels, syrups, slurries, suspensions and the like, for oralingestion by a subject to be treated. In some embodiments,pharmaceutical compositions for oral use are obtained using solidexcipients, optionally grinding a resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. Suitable excipients include, but are notlimited to, fillers such as sugars, including lactose, sucrose,mannitol, or sorbitol; cellulose preparations such as, for example,maize starch, wheat starch, rice starch, potato starch, gelatin, gumtragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodiumcarboxymethylcellulose; and/or polyvinylpyrrolidone (PVP). If desired,disintegrating agents may be added, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodiumalginate.

In some embodiments, dragee cores are provided with suitable coatings.In certain such embodiments, concentrated sugar solutions may be used,which may optionally contain gum arabic, talc, polyvinyl pyrrolidone,carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquersolutions, and suitable organic solvents or solvent mixtures. Dyestuffsor pigments may be added to the tablets or dragee coatings foridentification or to characterize doses of different combinations of oneor more compounds of the disclosure.

In some embodiments, pharmaceutical compositions of the disclosure whichcan be used orally include push-fit capsules made of gelatin, as well assoft, sealed capsules made of gelatin and a plasticizer, such asglycerol or sorbitol. In certain such embodiments, the push-fit capsulescan contain the active ingredients in an admixture with fillers such aslactose, binders such as starches, and/or lubricants such as talc ormagnesium stearate and, optionally, stabilizers. In soft capsules, oneor more compounds of the disclosure may be dissolved or suspended insuitable liquids, such as fatty oils, liquid paraffin, or liquidpolyethylene glycols. In addition, stabilizers may be added.

In some embodiments, the compositions of the disclosure may alsooptionally contain one or more opacifying agents and may be of acomposition such that they release the one or more compounds of thedisclosure only, or preferentially, in a certain portion of thegastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions that can be used include polymeric substances andwaxes. The compounds and compositions of this disclosure, or mixturesthereof, can also be in micro-encapsulated form, if appropriate, withone or more of the above-described excipients.

In some embodiments, one or more compounds or salts of the disclosuremay be formulated for parenteral administration by injection, e.g., byintramuscular, subcutaneous and intravenous injections, bolus injectionor continuous infusion. In some embodiments, compositions for injectioncan be presented in unit dosage form, e.g., in ampoules or in multi-dosecontainers, with an added preservative. In some embodiments, one or morecompounds or salts of the disclosure can take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and can containformulatory agents such as suspending, stabilizing and/or dispersingagents.

In some embodiments, pharmaceutical compositions for parenteraladministration include aqueous solutions of one or more compounds orsalts of the disclosure in water-soluble form. In certain suchembodiments, suspensions of one or more compounds or salts of thedisclosure can be prepared as appropriate oily injection suspensions.Suitable lipophilic solvents or vehicles include fatty oils such assesame oil, or synthetic fatty acid esters, such as ethyl oleate ortriglycerides, or liposomes. Aqueous injection suspensions may containsubstances which increase the viscosity of the suspension, such assodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, thesuspension may also contain suitable stabilizers or agents whichincrease the solubility of one or more compounds of the disclosure toallow for the preparation of highly concentrated solutions. Forinjection, one or more compounds or salts of the disclosure may beformulated in aqueous solutions, for example, physiologically compatiblebuffers such as Hanks's solution, Ringer's solution, or physiologicalsaline buffer.

In some embodiments, one or more compounds or salts of the disclosuremay be in powder form for constitution with a suitable vehicle, e.g.,sterile pyrogen-free water, before use.

In some embodiments, one or more compounds or salts of the disclosureare formulated for transmucosal absorption. Transmucosal absorption canoccur through any mucosa. Exemplary mucosa include: oral mucosa (e.g.,buccal mucosa and sublingual mucosa), nasal mucosa, rectal mucosa, andpulmonary mucosa. For transmucosal administration, penetrantsappropriate to the barrier to be permeated are used in the composition.Such penetrants are generally known in the art.

Methods of formulating compounds for transmucosal absorption are wellknown in the art. For example, a composition may be formulated forbuccal absorption using buccal tablets, lozenges, buccal powders, andbuccal spray solutions. A composition may be formulated for sublingualabsorption using sublingual tablets, sublingual films, liquids,sublingual powders, and sublingual spray solutions.

In some embodiments, the pharmaceutical compositions of the disclosureare for administration by inhalation. In some embodiments, thecomposition may be formulated for intranasal absorption through nasalsprays. In some embodiments, the composition may be formulated forpulmonary absorption through aerosolized compositions and inhalabledried powders. When formulated for sprays or aerosolized compositions, acomposition may be prepared with saline as a solution, employ benzylalcohol or other suitable preservatives, or include absorption promotersto enhance bioavailability, fluorocarbons, and/or other solubilizing ordispersing agents. In some embodiments, one or more compounds of thedisclosure are delivered in the form of an aerosol spray presentationfrom pressurized packs or a nebulizer, with the use of a suitablepropellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol the dosage unit may be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof e.g. gelatin for use in an inhaler or insufflator may be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

In some embodiments, one or more compounds or salts of the disclosurecan be formulated in rectal compositions such as suppositories orretention enemas, e.g., containing conventional suppository bases suchas cocoa butter or other glycerides.

In some embodiments, one or more compounds or salts of the disclosurecan be formulated for transdermal administration. Compositions fortransdermal administration include powders, sprays, ointments, pastes,creams, lotions, gels, solutions, patches, and inhalants. One or morecompounds of the disclosure may be mixed under sterile conditions with apharmaceutically acceptable carrier, and with any preservatives,buffers, or propellants that may be required. The ointments, pastes,creams, and gels may contain, in addition to one or more compounds andcompositions of this disclosure, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, perfumingagents, coloring agents, silicic acid, talc, and zinc oxide, or mixturesthereof.

In some embodiments, one or more compounds or salts of the disclosurecan be formulated as a depot composition. Such long acting compositionscan be administered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection.

In some embodiments, one or more compounds or salts of the disclosurecan be formulated with suitable polymeric or hydrophobic materials (forexample as an emulsion in an acceptable oil) or ion exchange resins, oras sparingly soluble derivatives, for example, as a sparingly solublesalt.

The pharmaceutical compositions of the disclosure can also comprisesuitable solid or gel phase carriers or excipients. Examples of suchcarriers or excipients include but are not limited to calcium carbonate,calcium phosphate, various sugars, starches, cellulose derivatives,gelatin, and polymers such as polyethylene glycols.

In some embodiments, one or more pharmaceutical compositions of thedisclosure are thermally-stable and sterile and suitable foradministration to a subject. In some embodiments, one or morepharmaceutical compositions of the disclosure are thermally stable atabout 4° C. for at least two years. In some embodiments, one or morepharmaceutical compositions of the disclosure are thermally stable atabout ambient temperature for at least two years. In some embodiments,one or more pharmaceutical compositions of the disclosure are thermallystable at about 37° C. for at least two years. In some embodiments, thepharmaceutical compositions of the disclosure are stable at ambienttemperature for at least 1 year, 2 years, 3 years, 4 years, 5 years, 6years, 7 years, 7 years, 8 years, 9 years or 10 years.

Pharmaceutical compositions of this disclosure include compositionswherein one or more compounds or salts of the disclosure are containedin a therapeutically effective or protective amount, i.e., an amounteffective to achieve its intended purpose. Of course, the actual amountof one or more compounds of the disclosure will depend on, among otherthings, its intended purpose. For example, when administered to cancersubjects as a cytoprotectant in conjunction with radiation orchemotherapy, such compositions will contain an amount of one or morecompounds of the disclosure effective to, inter alia, ameliorate theharmful effects of ionizing radiation or chemotherapeutic agents tonormal tissues, with minimal effect on the therapeutic purpose of theradiation or chemotherapy on the diseased tissues. When administered tosubjects suffering from diseases requiring bone marrow growth, such asmyelodysplastic syndromes (MDS), or requiring more rapid recovery ofbone marrow function following chemotherapy, compositions of thedisclosure will contain an amount of one or more compounds of thedisclosure effective to stimulate bone marrow production or function inthe subject being treated. Determination of an effective amount is wellwithin the capabilities of those skilled in the art, especially in lightof the detailed disclosure herein. In some embodiments, the compositionsof the disclosure comprise about 10 mg to about 10,000 mg of one or morecompounds or salts of the disclosure.

In some embodiments, the compounds, salts or compositions of thedisclosure are useful as cytoprotectants to selectively protect againstthe toxicities of ionizing radiation or chemotherapeutic agents. Incertain such embodiments, a circulating concentration of one or morecompounds of the disclosure (and/or and a metabolite thereof) of about 2μM to about 100 μM is effective as cytoprotectant. In certain suchembodiments, the concentration of one or more compounds of thedisclosure is about 5 μM to about 50 μM. Alternatively, or in additionto, a tissue concentration of one or more compounds of the disclosure(and/or a metabolite thereof) of about 4 μM to about 700 μM is effectiveas a cytoprotectant. In certain such embodiments, the effective tissueconcentration is about 20 μM to about 350 μM.

In some embodiments, the pharmaceutical compositions of this disclosurefurther comprise an antioxidant. In some embodiments, the pharmaceuticalcomposition is co-administered (sequentially, concurrently orseparately) with an antioxidant. In some embodiments, the antioxidant isa non-thiol antioxidant. In some embodiments, the antioxidant isselected from the group consisting of ascorbic acid, ascorbate, vitaminC, N-acetylcysteine, glutathione, lipoic acid, uric acid,alphα-tocopherol, γ-tocotrienol, vitamin E, beta-carotene, vitamin A,retinol, selenocysteine, cyanidine-3-glucoside, and ubiquinol. In someembodiments, the non-thiol antioxidant comprises α-tocopherol,β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol,γ-tocotrienol, δ-tocotrienol, vitamin E, carotene, beta-carotene,ascorbate, vitamin C, cyanidine-3-glucoside, selenocysteine, orcombinations thereof. In some embodiments, the non-thiol antioxidant isselected from the group consisting of α-tocopherol, β-tocopherol,γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol,δ-tocotrienol, vitamin E, carotene, beta-carotene, ascorbate, vitamin C,cyanidine-3-glucoside, selenocysteine, and combinations thereof. In someembodiments, the non-thiol antioxidant is selected from the groupconsisting of α-tocopherol, γ-tocotrienol, and selenocysteine. In someembodiments, the antioxidant is ascorbic acid. In some embodiments, theantioxidant is ascorbate. In some embodiments, the antioxidant isvitamin C. In some embodiments, the antioxidant is N-acetylcysteine. Insome embodiments, the antioxidant is glutathione. In some embodiments,the antioxidant is lipoic acid. In some embodiments, the antioxidant isuric acid. In some embodiments, the antioxidant is α-tocopherol. In someembodiments, the antioxidant is γ-tocotrienol. In some embodiments, theantioxidant is vitamin E. In some embodiments, the antioxidant isbeta-carotene. In some embodiments, the antioxidant is vitamin A. Insome embodiments, the antioxidant is retinol. In some embodiments, theantioxidant is vitamin A. In some embodiments, the antioxidant isselenocysteine. In some embodiments, the antioxidant iscyanidine-3-glucoside. In some embodiments, the antioxidant isubiquinol.

In some embodiments, the pharmaceutical composition of this disclosurecomprises any one of compounds 1-50 and an antioxidant. In someembodiments, the pharmaceutical composition of this disclosure comprisescompound 42 and an antioxidant. In some embodiments, the pharmaceuticalcomposition of this disclosure comprises compound 50 and an antioxidant.In some embodiments, the pharmaceutical composition of this disclosurecomprises any one of compounds 1-50 and a non-thiol antioxidant. In someembodiments, the pharmaceutical composition of this disclosure comprisescompound 42 and a non-thiol antioxidant. In some embodiments, thepharmaceutical composition of this disclosure comprises compound 50 anda non-thiol antioxidant. In some embodiments, the pharmaceuticalcomposition of this disclosure comprises any one of compounds 1-50 and anon-thiol antioxidant, wherein the antioxidant is selected from thegroup consisting of α-tocopherol, γ-tocotrienol, and selenocysteine. Insome embodiments, the pharmaceutical composition of this disclosurecomprises compound 42 and a non-thiol antioxidant, wherein theantioxidant is selected from the group consisting of α-tocopherol,γ-tocotrienol, and selenocysteine. In some embodiments, thepharmaceutical composition of this disclosure comprises compound 50 anda non-thiol antioxidant, wherein the antioxidant is selected from thegroup consisting of α-tocopherol, γ-tocotrienol, and selenocysteine. Insome embodiments, the pharmaceutical composition of this disclosurecomprises any one of compounds 1-50 and α-tocopherol. In someembodiments, the pharmaceutical composition of this disclosure comprisescompound 42 and α-tocopherol. In some embodiments, the pharmaceuticalcomposition of this disclosure comprises compound 50 and α-tocopherol.In some embodiments, the pharmaceutical composition of this disclosurecomprises any one of compounds 1-50 and γ-tocotrienol. In someembodiments, the pharmaceutical composition of this disclosure comprisescompound 42 and γ-tocotrienol. In some embodiments, the pharmaceuticalcomposition of this disclosure comprises compound 50 and γ-tocotrienol.In some embodiments, the pharmaceutical composition of this disclosurecomprises any one of compounds 1-50 and selenocysteine. In someembodiments, the pharmaceutical composition of this disclosure comprisescompound 42 and selenocysteine. In some embodiments, the pharmaceuticalcomposition of this disclosure comprises compound 50 and selenocysteine.

In some embodiments, the pharmaceutical composition of this disclosurein combination with an antioxidant exhibits a synergisticradioprotective effect in mammals, mammalian tissues and/or culturedmammalian cells. In some embodiments, the pharmaceutical composition ofthis disclosure in combination with an antioxidant exhibits an additiveradioprotective effect in mammals, mammalian tissues and/or culturedmammalian cells. In some embodiments, the pharmaceutical composition ofthis disclosure comprises a prodrug and a non-thiol antioxidant andexhibits a synergistic radioprotective effect in mammals, mammaliantissues and/or cultured mammalian cells. In some embodiments, thepharmaceutical composition of this disclosure in combination with anantioxidant reduces the side effects of the pharmaceutical composition.

Methods of Administration

Suitable routes of administration for one or more compounds, salts orcompositions of this disclosure include, but are not limited to,inhalation, topical, cutaneous, transdermal, oral, rectal, transmucosal,intestinal, topical, cutaneous and parenteral, administration, includingintramuscular, subcutaneous and intravenous injections. Appropriatemethods of administering one or more compounds or compositions of thedisclosure to a subject will depend, for example, on the age of thesubject , the subject's physiological status including blood pressure,whether or not the subject is capable of taking oral medication, whetherthe subject is active or inactive at the time of administering, whetherthe subject is experiencing symptoms of a disease or condition at thetime of administering, the extent of the symptoms, and the chemical andbiological properties of the compound or composition (e.g. solubility,digestibility, bioavailability, stability and toxicity). In a preferredembodiment, the compounds or compositions of the disclosure are orallyadministered.

For any mode of administration, the actual amount of one or morecompounds, salts or compositions of the disclosure delivered, as well asthe dosing schedule necessary to achieve the advantageouspharmacokinetic profiles described herein, will be depend, in part, onsuch factors as the bioavailability of the one or more compounds of thedisclosure, the disorder being treated or the potential radiationexposure being addressed, the desired therapeutic amount, and otherfactors that will be apparent to those of skill in the art. The actualamount delivered and an appropriate dosing schedule can be readilydetermined by those of skill without undue experimentation by monitoringthe blood plasma levels of the administered compounds of the disclosure,and adjusting the dosage or dosing schedule as necessary to achieve thedesired pharmacokinetic profile. In some embodiments, one or morecompounds or compositions of the disclosure are administered once perday. In some embodiments, one or more compounds or compositions of thedisclosure are administered once per day for several years. In someembodiments, one or more compounds, salts or compositions of thedisclosure are administered once per day for one year, two years, threeyears, four years, five years, six years, seven years, eight years, nineyears, ten years, 15 years, 20 years, 25 years, 30 years, 35 years, 40years, 45 years, or 50 years. In some embodiments, one or more compoundsor compositions of the disclosure are administered multiple times perday, e.g., two or three times per day. In some embodiments, one or morecompounds, salts or compositions of the disclosure are administeredmultiple times per day for several years. In some embodiments, one ormore compounds, salts or compositions of the disclosure are administeredmultiple times per day for one year, two years, three years, four years,five years, six years, seven years, eight years, nine years, ten years,15 years, 20 years, 25 years, 30 years, 35 years, 40 years, 45 years, or50 years.

In some embodiments, one or more compounds, salts or compositions of thedisclosure may be administered singly, in combinationsimultaneously/concurrently, separately, or sequentially with othercompounds or compositions, and/or in combinationsimultaneously/concurrently, separately, or sequentially with othertherapeutic agents, including cancer chemotherapeutic agents. In someembodiments, one or more compounds or salts of the disclosure may beadministered alone or in the form of a pharmaceutical composition,wherein the compound or salt of the disclosure is in admixture with oneor more pharmaceutically acceptable carriers, excipients or diluents.

In some embodiments, the one or more compounds, salts or compositions ofthe disclosure are orally administered during the administration ofradiation therapy or potential exposure to other sources of ionizingradiation. In some embodiments, the one or more compounds, salts orcompositions of the disclosure are subcutaneously administered duringthe administration of radiation therapy or potential exposure to othersources of ionizing radiation. In some embodiments, the one or morecompounds, salts or compositions of the disclosure are intravenouslyadministered during the administration of radiation therapy or potentialexposure to other sources of ionizing radiation. In some embodiments,the one or more compounds, salts or compositions of the disclosure aretopically administered during the administration of radiation therapy orpotential exposure to other sources of ionizing radiation. In someembodiments, the one or more compounds, salts or compositions of thedisclosure are cutaneously administered during the administration ofradiation therapy or potential exposure to other sources of ionizingradiation. In some embodiments, the one or more compounds, salts orcompositions of the disclosure are orally administered during theadministration of chemotherapy. In some embodiments, the one or morecompounds, salts or compositions of the disclosure are subcutaneouslyadministered during the administration of chemotherapy. In someembodiments, the one or more compounds, salts or compositions of thedisclosure are intravenously administered during the administration ofchemotherapy. In some embodiments, the one or more compounds, salts orcompositions of the disclosure are topically administered during theadministration of chemotherapy. In some embodiments, the one or morecompounds, salts or compositions of the disclosure are cutaneouslyadministered during the administration of chemotherapy.

In some embodiments, the one or more compounds, salts or compositions ofthe disclosure are administered orally at least about three hours priorto the administration of radiation therapy or potential exposure toother sources of ionizing radiation. In some embodiments, the one ormore compounds, salts or compositions of the disclosure are orallyadministered at least about 15 minutes prior to the administration ofradiation therapy or potential exposure to other sources of ionizingradiation, such as at least about 5 minutes, or about 5 minutes to about30 minutes prior to the administration of radiation therapy or potentialexposure to other sources of ionizing radiation. In some embodiments,the one or more compounds, salts or compositions of the disclosure areorally administered at least about 30 minutes prior to theadministration of radiation therapy or potential exposure to othersources of ionizing radiation, such as at least about 15 minutes, orabout 15 minutes to about 60 minutes prior to the administration ofradiation therapy or potential exposure to other sources of ionizingradiation. In some embodiments, the one or more compounds, salts orcompositions of the disclosure are orally administered at least about 60minutes prior to the administration of radiation therapy or potentialexposure to other sources of ionizing radiation, such as at least about30 minutes, or about 30 minutes to about 120 minutes prior to theadministration of radiation therapy or potential exposure to othersources of ionizing radiation. In some embodiments, the one or morecompounds, salts or compositions of the disclosure are orallyadministered at least about 2 hours prior to the administration ofradiation therapy or potential exposure to other sources of ionizingradiation, such as at least about 1 hour, or about 1 hour to about 4hours prior to the administration of radiation therapy or potentialexposure to other sources of ionizing radiation. In some embodiments,the one or more compounds, salts or compositions of the disclosure areorally administered at least about 4 hours prior to the administrationof radiation therapy or potential exposure to other sources of ionizingradiation, such as at least about 2 hours, or about 2 hours to about 8hours prior to the administration of radiation therapy or potentialexposure to other sources of ionizing radiation. In some embodiments,the one or more compounds, salts or compositions of the disclosure areorally administered at least about 6 hours prior to the administrationof radiation therapy or potential exposure to other sources of ionizingradiation, such as at least about 8 hours, or about 8 hours to about 12hours prior to the administration of radiation therapy or potentialexposure to other sources of ionizing radiation.

In some embodiments, the one or more compounds, salts or compositions ofthe disclosure are administered subcutaneously at least about threehours prior to the administration of radiation therapy or potentialexposure to other sources of ionizing radiation. In some embodiments,the one or more compounds, salts or compositions of the disclosure aresubcutaneously administered at least about 15 minutes prior to theadministration of radiation therapy or potential exposure to othersources of ionizing radiation, such as at least about 5 minutes, orabout 5 minutes to about 30 minutes prior to the administration ofradiation therapy or potential exposure to other sources of ionizingradiation. In some embodiments, the one or more compounds, salts orcompositions of the disclosure are subcutaneously administered at leastabout 30 minutes prior to the administration of radiation therapy orpotential exposure to other sources of ionizing radiation, such as atleast about 15 minutes, or about 15 minutes to about 60 minutes prior tothe administration of radiation therapy or potential exposure to othersources of ionizing radiation. In some embodiments, the one or morecompounds, salts or compositions of the disclosure are subcutaneouslyadministered at least about 60 minutes prior to the administration ofradiation therapy or potential exposure to other sources of ionizingradiation, such as at least about 30 minutes, or about 30 minutes toabout 120 minutes prior to the administration of radiation therapy orpotential exposure to other sources of ionizing radiation. In someembodiments, the one or more compounds, salts or compositions of thedisclosure are subcutaneously administered at least about 2 hours priorto the administration of radiation therapy or potential exposure toother sources of ionizing radiation, such as at least about 1 hour, orabout 1 hour to about 4 hours prior to the administration of radiationtherapy or potential exposure to other sources of ionizing radiation. Insome embodiments, the one or more compounds, salts or compositions ofthe disclosure are subcutaneously administered at least about 4 hoursprior to the administration of radiation therapy or potential exposureto other sources of ionizing radiation, such as at least about 2 hours,or about 2 hours to about 8 hours prior to the administration ofradiation therapy or potential exposure to other sources of ionizingradiation. In some embodiments, the one or more compounds, salts orcompositions of the disclosure are subcutaneously administered at leastabout 6 hours prior to the administration of radiation therapy orpotential exposure to other sources of ionizing radiation, such as atleast about 8 hours, or about 8 hours to about 12 hours prior to theadministration of radiation therapy or potential exposure to othersources of ionizing radiation.

In some embodiments, the one or more compounds, salts or compositions ofthe disclosure are administered intravenously at least about three hoursprior to the administration of radiation therapy or potential exposureto other sources of ionizing radiation. In some embodiments, the one ormore compounds, salts or compositions of the disclosure areintravenously administered at least about 15 minutes prior to theadministration of radiation therapy or potential exposure to othersources of ionizing radiation, such as at least about 5 minutes, orabout 5 minutes to about 30 minutes prior to the administration ofradiation therapy or potential exposure to other sources of ionizingradiation. In some embodiments, the one or more compounds, salts orcompositions of the disclosure are intravenously administered at leastabout 30 minutes prior to the administration of radiation therapy orpotential exposure to other sources of ionizing radiation, such as atleast about 15 minutes, or about 15 minutes to about 60 minutes prior tothe administration of radiation therapy or potential exposure to othersources of ionizing radiation. In some embodiments, the one or morecompounds, salts or compositions of the disclosure are intravenouslyadministered at least about 60 minutes prior to the administration ofradiation therapy or potential exposure to other sources of ionizingradiation, such as at least about 30 minutes, or about 30 minutes toabout 120 minutes prior to the administration of radiation therapy orpotential exposure to other sources of ionizing radiation. In someembodiments, the one or more compounds, salts or compositions of thedisclosure are intravenously administered at least about 2 hours priorto the administration of radiation therapy or potential exposure toother sources of ionizing radiation, such as at least about 1 hour, orabout 1 hour to about 4 hours prior to the administration of radiationtherapy or potential exposure to other sources of ionizing radiation. Insome embodiments, the one or more compounds, salts or compositions ofthe disclosure are intravenously administered at least about 4 hoursprior to the administration of radiation therapy or potential exposureto other sources of ionizing radiation, such as at least about 2 hours,or about 2 hours to about 8 hours prior to the administration ofradiation therapy or potential exposure to other sources of ionizingradiation. In some embodiments, the one or more compounds, salts orcompositions of the disclosure are intravenously administered at leastabout 6 hours prior to the administration of radiation therapy orpotential exposure to other sources of ionizing radiation, such as atleast about 8 hours, or about 8 hours to about 12 hours prior to theadministration of radiation therapy or potential exposure to othersources of ionizing radiation.

In some embodiments, the one or more compounds, salts or compositions ofthe disclosure are administered topically at least about three hoursprior to the administration of radiation therapy or potential exposureto other sources of ionizing radiation. In some embodiments, the one ormore compounds, salts or compositions of the disclosure are topicallyadministered at least about 15 minutes prior to the administration ofradiation therapy or potential exposure to other sources of ionizingradiation, such as at least about 5 minutes, or about 5 minutes to about30 minutes prior to the administration of radiation therapy or potentialexposure to other sources of ionizing radiation. In some embodiments,the one or more compounds, salts or compositions of the disclosure aretopically administered at least about 30 minutes prior to theadministration of radiation therapy or potential exposure to othersources of ionizing radiation, such as at least about 15 minutes, orabout 15 minutes to about 60 minutes prior to the administration ofradiation therapy or potential exposure to other sources of ionizingradiation. In some embodiments, the one or more compounds, salts orcompositions of the disclosure are topically administered at least about60 minutes prior to the administration of radiation therapy or potentialexposure to other sources of ionizing radiation, such as at least about30 minutes, or about 30 minutes to about 120 minutes prior to theadministration of radiation therapy or potential exposure to othersources of ionizing radiation. In some embodiments, the one or morecompounds, salts or compositions of the disclosure are topicallyadministered at least about 2 hours prior to the administration ofradiation therapy or potential exposure to other sources of ionizingradiation, such as at least about 1 hour, or about 1 hour to about 4hours prior to the administration of radiation therapy or potentialexposure to other sources of ionizing radiation. In some embodiments,the one or more compounds, salts or compositions of the disclosure aretopically administered at least about 4 hours prior to theadministration of radiation therapy or potential exposure to othersources of ionizing radiation, such as at least about 2 hours, or about2 hours to about 8 hours prior to the administration of radiationtherapy or potential exposure to other sources of ionizing radiation. Insome embodiments, the one or more compounds, salts or compositions ofthe disclosure are topically administered at least about 6 hours priorto the administration of radiation therapy or potential exposure toother sources of ionizing radiation, such as at least about 8 hours, orabout 8 hours to about 12 hours prior to the administration of radiationtherapy or potential exposure to other sources of ionizing radiation.

In some embodiments, the one or more compounds, salts or compositions ofthe disclosure are administered cutaneously at least about three hoursprior to the administration of radiation therapy or potential exposureto other sources of ionizing radiation. In some embodiments, the one ormore compounds, salts or compositions of the disclosure are cutaneouslyadministered at least about 15 minutes prior to the administration ofradiation therapy or potential exposure to other sources of ionizingradiation, such as at least about 5 minutes, or about 5 minutes to about30 minutes prior to the administration of radiation therapy or potentialexposure to other sources of ionizing radiation. In some embodiments,the one or more compounds, salts or compositions of the disclosure arecutaneously administered at least about 30 minutes prior to theadministration of radiation therapy or potential exposure to othersources of ionizing radiation, such as at least about 15 minutes, orabout 15 minutes to about 60 minutes prior to the administration ofradiation therapy or potential exposure to other sources of ionizingradiation. In some embodiments, the one or more compounds, salts orcompositions of the disclosure are cutaneously administered at leastabout 60 minutes prior to the administration of radiation therapy orpotential exposure to other sources of ionizing radiation, such as atleast about 30 minutes, or about 30 minutes to about 120 minutes priorto the administration of radiation therapy or potential exposure toother sources of ionizing radiation. In some embodiments, the one ormore compounds, salts or compositions of the disclosure are cutaneouslyadministered at least about 2 hours prior to the administration ofradiation therapy or potential exposure to other sources of ionizingradiation, such as at least about 1 hour, or about 1 hour to about 4hours prior to the administration of radiation therapy or potentialexposure to other sources of ionizing radiation. In some embodiments,the one or more compounds, salts or compositions of the disclosure arecutaneously administered at least about 4 hours prior to theadministration of radiation therapy or potential exposure to othersources of ionizing radiation, such as at least about 2 hours, or about2 hours to about 8 hours prior to the administration of radiationtherapy or potential exposure to other sources of ionizing radiation. Insome embodiments, the one or more compounds, salts or compositions ofthe disclosure are cutaneously administered at least about 6 hours priorto the administration of radiation therapy or potential exposure toother sources of ionizing radiation, such as at least about 8 hours, orabout 8 hours to about 12 hours prior to the administration of radiationtherapy or potential exposure to other sources of ionizing radiation.

In some embodiments, the one or more compounds, salts or compositions ofthe disclosure are administered orally at least about three hours priorto the administration of chemotherapy. In some embodiments, the one ormore compounds, salts or compositions of the disclosure are orallyadministered at least about 15 minutes prior to the administration ofchemotherapy, such as at least about 5 minutes, or about 5 minutes toabout 30 minutes prior to the administration of chemotherapy. In someembodiments, the one or more compounds, salts or compositions of thedisclosure are orally administered at least about 30 minutes prior tothe administration of chemotherapy, such as at least about 15 minutes,or about 15 minutes to about 60 minutes prior to the administration ofchemotherapy. In some embodiments, the one or more compounds, salts orcompositions of the disclosure are orally administered at least about 60minutes prior to the administration of chemotherapy, such as at leastabout 30 minutes, or about 30 minutes to about 120 minutes prior to theadministration of chemotherapy. In some embodiments, the one or morecompounds, salts or compositions of the disclosure are orallyadministered at least about 2 hours prior to the administration ofchemotherapy, such as at least about 1 hour, or about 1 hour to about 4hours prior to the administration of chemotherapy. In some embodiments,the one or more compounds, salts or compositions of the disclosure areorally administered at least about 4 hours prior to the administrationof chemotherapy, such as at least about 2 hours, or about 2 hours toabout 8 hours prior to the administration of chemotherapy. In someembodiments, the one or more compounds, salts or compositions of thedisclosure are orally administered at least about 6 hours prior to theadministration of chemotherapy, such as at least about 8 hours, or about8 hours to about 12 hours prior to the administration of chemotherapy.

In some embodiments, the one or more compounds, salts or compositions ofthe disclosure are administered subcutaneously at least about threehours prior to the administration of chemotherapy. In some embodiments,the one or more compounds, salts or compositions of the disclosure aresubcutaneously administered at least about 15 minutes prior to theadministration of chemotherapy, such as at least about 5 minutes, orabout 5 minutes to about 30 minutes prior to the administration ofchemotherapy. In some embodiments, the one or more compounds, salts orcompositions of the disclosure are subcutaneously administered at leastabout 30 minutes prior to the administration of chemotherapy, such as atleast about 15 minutes, or about 15 minutes to about 60 minutes prior tothe administration of chemotherapy. In some embodiments, the one or morecompounds, salts or compositions of the disclosure are subcutaneouslyadministered at least about 60 minutes prior to the administration ofchemotherapy, such as at least about 30 minutes, or about 30 minutes toabout 120 minutes prior to the administration of chemotherapy. In someembodiments, the one or more compounds, salts or compositions of thedisclosure are subcutaneously administered at least about 2 hours priorto the administration of chemotherapy, such as at least about 1 hour, orabout 1 hour to about 4 hours prior to the administration ofchemotherapy. In some embodiments, the one or more compounds, salts orcompositions of the disclosure are subcutaneously administered at leastabout 4 hours prior to the administration of chemotherapy, such as atleast about 2 hours, or about 2 hours to about 8 hours prior to theadministration of chemotherapy. In some embodiments, the one or morecompounds, salts or compositions of the disclosure are subcutaneouslyadministered at least about 6 hours prior to the administration ofchemotherapy, such as at least about 8 hours, or about 8 hours to about12 hours prior to the administration of chemotherapy.

In some embodiments, the one or more compounds, salts or compositions ofthe disclosure are administered intravenously at least about three hoursprior to the administration of chemotherapy. In some embodiments, theone or more compounds, salts or compositions of the disclosure areintravenously administered at least about 15 minutes prior to theadministration of chemotherapy, such as at least about 5 minutes, orabout 5 minutes to about 30 minutes prior to the administration ofchemotherapy. In some embodiments, the one or more compounds, salts orcompositions of the disclosure are intravenously administered at leastabout 30 minutes prior to the administration of chemotherapy, such as atleast about 15 minutes, or about 15 minutes to about 60 minutes prior tothe administration of chemotherapy. In some embodiments, the one or morecompounds, salts or compositions of the disclosure are intravenouslyadministered at least about 60 minutes prior to the administration ofchemotherapy, such as at least about 30 minutes, or about 30 minutes toabout 120 minutes prior to the administration of chemotherapy. In someembodiments, the one or more compounds, salts or compositions of thedisclosure are intravenously administered at least about 2 hours priorto the administration of chemotherapy, such as at least about 1 hour, orabout 1 hour to about 4 hours prior to the administration ofchemotherapy. In some embodiments, the one or more compounds, salts orcompositions of the disclosure are intravenously administered at leastabout 4 hours prior to the administration of chemotherapy, such as atleast about 2 hours, or about 2 hours to about 8 hours prior to theadministration of chemotherapy. In some embodiments, the one or morecompounds, salts or compositions of the disclosure are intravenouslyadministered at least about 6 hours prior to the administration ofchemotherapy, such as at least about 8 hours, or about 8 hours to about12 hours prior to the administration of chemotherapy.

In some embodiments, the one or more compounds, salts or compositions ofthe disclosure are administered topically at least about three hoursprior to the administration of chemotherapy. In some embodiments, theone or more compounds, salts or compositions of the disclosure aretopically administered at least about 15 minutes prior to theadministration of chemotherapy, such as at least about 5 minutes, orabout 5 minutes to about 30 minutes prior to the administration ofchemotherapy. In some embodiments, the one or more compounds, salts orcompositions of the disclosure are topically administered at least about30 minutes prior to the administration of chemotherapy, such as at leastabout 15 minutes, or about 15 minutes to about 60 minutes prior to theadministration of chemotherapy. In some embodiments, the one or morecompounds, salts or compositions of the disclosure are topicallyadministered at least about 60 minutes prior to the administration ofchemotherapy, such as at least about 30 minutes, or about 30 minutes toabout 120 minutes prior to the administration of chemotherapy. In someembodiments, the one or more compounds, salts or compositions of thedisclosure are topically administered at least about 2 hours prior tothe administration of chemotherapy, such as at least about 1 hour, orabout 1 hour to about 4 hours prior to the administration ofchemotherapy. In some embodiments, the one or more compounds, salts orcompositions of the disclosure are topically administered at least about4 hours prior to the administration of chemotherapy, such as at leastabout 2 hours, or about 2 hours to about 8 hours prior to theadministration of chemotherapy. In some embodiments, the one or morecompounds, salts or compositions of the disclosure are topicallyadministered at least about 6 hours prior to the administration ofchemotherapy, such as at least about 8 hours, or about 8 hours to about12 hours prior to the administration of chemotherapy.

In some embodiments, the one or more compounds, salts or compositions ofthe disclosure are administered cutaneously at least about three hoursprior to the administration of chemotherapy. In some embodiments, theone or more compounds, salts or compositions of the disclosure arecutaneously administered at least about 15 minutes prior to theadministration of chemotherapy, such as at least about 5 minutes, orabout 5 minutes to about 30 minutes prior to the administration ofchemotherapy. In some embodiments, the one or more compounds, salts orcompositions of the disclosure are cutaneously administered at leastabout 30 minutes prior to the administration of chemotherapy, such as atleast about 15 minutes, or about 15 minutes to about 60 minutes prior tothe administration of chemotherapy. In some embodiments, the one or morecompounds, salts or compositions of the disclosure are cutaneouslyadministered at least about 60 minutes prior to the administration ofchemotherapy, such as at least about 30 minutes, or about 30 minutes toabout 120 minutes prior to the administration of chemotherapy. In someembodiments, the one or more compounds, salts or compositions of thedisclosure are cutaneously administered at least about 2 hours prior tothe administration of chemotherapy, such as at least about 1 hour, orabout 1 hour to about 4 hours prior to the administration ofchemotherapy. In some embodiments, the one or more compounds, salts orcompositions of the disclosure are cutaneously administered at leastabout 4 hours prior to the administration of chemotherapy, such as atleast about 2 hours, or about 2 hours to about 8 hours prior to theadministration of chemotherapy. In some embodiments, the one or morecompounds, salts or compositions of the disclosure are cutaneouslyadministered at least about 6 hours prior to the administration ofchemotherapy, such as at least about 8 hours, or about 8 hours to about12 hours prior to the administration of chemotherapy.

In some embodiments, the prodrugs or double prodrugs of the disclosureare administered orally at least about three hours prior to theadministration of radiation therapy or potential exposure to othersources of ionizing radiation. In some embodiments, the prodrugs ordouble prodrugs of the disclosure are orally administered at least about15 minutes prior to the administration of radiation therapy or potentialexposure to other sources of ionizing radiation, such as at least about5 minutes, or about 5 minutes to about 30 minutes prior to theadministration of radiation therapy or potential exposure to othersources of ionizing radiation. In some embodiments, the prodrugs ordouble prodrugs of the disclosure are orally administered at least about30 minutes prior to the administration of radiation therapy or potentialexposure to other sources of ionizing radiation, such as at least about15 minutes, or about 15 minutes to about 60 minutes prior to theadministration of radiation therapy or potential exposure to othersources of ionizing radiation. In some embodiments, the o prodrugs ordouble prodrugs of the disclosure are orally administered at least about60 minutes prior to the administration of radiation therapy or potentialexposure to other sources of ionizing radiation, such as at least about30 minutes, or about 30 minutes to about 120 minutes prior to theadministration of radiation therapy or potential exposure to othersources of ionizing radiation. In some embodiments, the prodrugs ordouble prodrugs of the disclosure are orally administered at least about2 hours prior to the administration of radiation therapy or potentialexposure to other sources of ionizing radiation, such as at least about1 hour, or about 1 hour to about 4 hours prior to the administration ofradiation therapy or potential exposure to other sources of ionizingradiation. In some embodiments, the prodrugs or double prodrugs of thedisclosure are orally administered at least about 4 hours prior to theadministration of radiation therapy or potential exposure to othersources of ionizing radiation, such as at least about 2 hours, or about2 hours to about 8 hours prior to the administration of radiationtherapy or potential exposure to other sources of ionizing radiation. Insome embodiments, the prodrugs or double prodrugs of the disclosure areorally administered at least about 6 hours prior to the administrationof radiation therapy or potential exposure to other sources of ionizingradiation, such as at least about 8 hours, or about 8 hours to about 12hours prior to the administration of radiation therapy or potentialexposure to other sources of ionizing radiation.

In some embodiments, the prodrugs or double prodrugs of the disclosureare administered subcutaneously at least about three hours prior to theadministration of radiation therapy or potential exposure to othersources of ionizing radiation. In some embodiments, the prodrugs ordouble prodrugs of the disclosure are subcutaneously administered atleast about 15 minutes prior to the administration of radiation therapyor potential exposure to other sources of ionizing radiation, such as atleast about 5 minutes, or about 5 minutes to about 30 minutes prior tothe administration of radiation therapy or potential exposure to othersources of ionizing radiation. In some embodiments, the prodrugs ordouble prodrugs of the disclosure are subcutaneously administered atleast about 30 minutes prior to the administration of radiation therapyor potential exposure to other sources of ionizing radiation, such as atleast about 15 minutes, or about 15 minutes to about 60 minutes prior tothe administration of radiation therapy or potential exposure to othersources of ionizing radiation. In some embodiments, the prodrugs ordouble prodrugs of the disclosure are subcutaneously administered atleast about 60 minutes prior to the administration of radiation therapyor potential exposure to other sources of ionizing radiation, such as atleast about 30 minutes, or about 30 minutes to about 120 minutes priorto the administration of radiation therapy or potential exposure toother sources of ionizing radiation. In some embodiments, the prodrugsor double prodrugs of the disclosure are subcutaneously administered atleast about 2 hours prior to the administration of radiation therapy orpotential exposure to other sources of ionizing radiation, such as atleast about 1 hour, or about 1 hour to about 4 hours prior to theadministration of radiation therapy or potential exposure to othersources of ionizing radiation. In some embodiments, the prodrugs ordouble prodrugs of the disclosure are subcutaneously administered atleast about 4 hours prior to the administration of radiation therapy orpotential exposure to other sources of ionizing radiation, such as atleast about 2 hours, or about 2 hours to about 8 hours prior to theadministration of radiation therapy or potential exposure to othersources of ionizing radiation. In some embodiments, prodrugs or doubleprodrugs of the disclosure are subcutaneously administered at leastabout 6 hours prior to the administration of radiation therapy orpotential exposure to other sources of ionizing radiation, such as atleast about 8 hours, or about 8 hours to about 12 hours prior to theadministration of radiation therapy or potential exposure to othersources of ionizing radiation.

In some embodiments, the prodrugs or double prodrugs compositions of thedisclosure are administered intravenously at least about three hoursprior to the administration of radiation therapy or potential exposureto other sources of ionizing radiation. In some embodiments, theprodrugs or double prodrugs of the disclosure are intravenouslyadministered at least about 15 minutes prior to the administration ofradiation therapy or potential exposure to other sources of ionizingradiation, such as at least about 5 minutes, or about 5 minutes to about30 minutes prior to the administration of radiation therapy or potentialexposure to other sources of ionizing radiation. In some embodiments,the prodrugs or double prodrugs of the disclosure are intravenouslyadministered at least about 30 minutes prior to the administration ofradiation therapy or potential exposure to other sources of ionizingradiation, such as at least about 15 minutes, or about 15 minutes toabout 60 minutes prior to the administration of radiation therapy orpotential exposure to other sources of ionizing radiation. In someembodiments, the one or more compounds, salts or compositions of thedisclosure are intravenously administered at least about 60 minutesprior to the administration of radiation therapy or potential exposureto other sources of ionizing radiation, such as at least about 30minutes, or about 30 minutes to about 120 minutes prior to theadministration of radiation therapy or potential exposure to othersources of ionizing radiation. In some embodiments, the prodrugs ordouble prodrugs of the disclosure are intravenously administered atleast about 2 hours prior to the administration of radiation therapy orpotential exposure to other sources of ionizing radiation, such as atleast about 1 hour, or about 1 hour to about 4 hours prior to theadministration of radiation therapy or potential exposure to othersources of ionizing radiation. In some embodiments, the prodrugs ordouble prodrugs of the disclosure are intravenously administered atleast about 4 hours prior to the administration of radiation therapy orpotential exposure to other sources of ionizing radiation, such as atleast about 2 hours, or about 2 hours to about 8 hours prior to theadministration of radiation therapy or potential exposure to othersources of ionizing radiation. In some embodiments, the prodrugs ordouble prodrugs of the disclosure are intravenously administered atleast about 6 hours prior to the administration of radiation therapy orpotential exposure to other sources of ionizing radiation, such as atleast about 8 hours, or about 8 hours to about 12 hours prior to theadministration of radiation therapy or potential exposure to othersources of ionizing radiation.

In some embodiments, the prodrugs or double prodrugs of the disclosureare administered topically at least about three hours prior to theadministration of radiation therapy or potential exposure to othersources of ionizing radiation. In some embodiments, the prodrugs ordouble prodrugs of the disclosure are topically administered at leastabout 15 minutes prior to the administration of radiation therapy orpotential exposure to other sources of ionizing radiation, such as atleast about 5 minutes, or about 5 minutes to about 30 minutes prior tothe administration of radiation therapy or potential exposure to othersources of ionizing radiation. In some embodiments, the prodrugs ordouble prodrugs of the disclosure are topically administered at leastabout 30 minutes prior to the administration of radiation therapy orpotential exposure to other sources of ionizing radiation, such as atleast about 15 minutes, or about 15 minutes to about 60 minutes prior tothe administration of radiation therapy or potential exposure to othersources of ionizing radiation. In some embodiments, the prodrugs ordouble prodrugs of the disclosure are topically administered at leastabout 60 minutes prior to the administration of radiation therapy orpotential exposure to other sources of ionizing radiation, such as atleast about 30 minutes, or about 30 minutes to about 120 minutes priorto the administration of radiation therapy or potential exposure toother sources of ionizing radiation. In some embodiments, the prodrugsor double prodrugs of the disclosure are topically administered at leastabout 2 hours prior to the administration of radiation therapy orpotential exposure to other sources of ionizing radiation, such as atleast about 1 hour, or about 1 hour to about 4 hours prior to theadministration of radiation therapy or potential exposure to othersources of ionizing radiation. In some embodiments, the prodrugs ordouble prodrugs of the disclosure are topically administered at leastabout 4 hours prior to the administration of radiation therapy orpotential exposure to other sources of ionizing radiation, such as atleast about 2 hours, or about 2 hours to about 8 hours prior to theadministration of radiation therapy or potential exposure to othersources of ionizing radiation. In some embodiments, the prodrugs ordouble prodrugs of the disclosure are topically administered at leastabout 6 hours prior to the administration of radiation therapy orpotential exposure to other sources of ionizing radiation, such as atleast about 8 hours, or about 8 hours to about 12 hours prior to theadministration of radiation therapy or potential exposure to othersources of ionizing radiation.

In some embodiments, the prodrugs or double prodrugs of the disclosureare administered cutaneously at least about three hours prior to theadministration of radiation therapy or potential exposure to othersources of ionizing radiation. In some embodiments, the prodrugs ordouble prodrugs of the disclosure are cutaneously administered at leastabout 15 minutes prior to the administration of radiation therapy orpotential exposure to other sources of ionizing radiation, such as atleast about 5 minutes, or about 5 minutes to about 30 minutes prior tothe administration of radiation therapy or potential exposure to othersources of ionizing radiation. In some embodiments, the prodrugs ordouble prodrugs of the disclosure are cutaneously administered at leastabout 30 minutes prior to the administration of radiation therapy orpotential exposure to other sources of ionizing radiation, such as atleast about 15 minutes, or about 15 minutes to about 60 minutes prior tothe administration of radiation therapy or potential exposure to othersources of ionizing radiation. In some embodiments, the prodrugs ordouble prodrugs of the disclosure are cutaneously administered at leastabout 60 minutes prior to the administration of radiation therapy orpotential exposure to other sources of ionizing radiation, such as atleast about 30 minutes, or about 30 minutes to about 120 minutes priorto the administration of radiation therapy or potential exposure toother sources of ionizing radiation. In some embodiments, the prodrugsor double prodrugs of the disclosure are cutaneously administered atleast about 2 hours prior to the administration of radiation therapy orpotential exposure to other sources of ionizing radiation, such as atleast about 1 hour, or about 1 hour to about 4 hours prior to theadministration of radiation therapy or potential exposure to othersources of ionizing radiation. In some embodiments, the prodrugs ordouble prodrugs of the disclosure are cutaneously administered at leastabout 4 hours prior to the administration of radiation therapy orpotential exposure to other sources of ionizing radiation, such as atleast about 2 hours, or about 2 hours to about 8 hours prior to theadministration of radiation therapy or potential exposure to othersources of ionizing radiation. In some embodiments, the prodrugs ordouble prodrugs of the disclosure are cutaneously administered at leastabout 6 hours prior to the administration of radiation therapy orpotential exposure to other sources of ionizing radiation, such as atleast about 8 hours, or about 8 hours to about 12 hours prior to theadministration of radiation therapy or potential exposure to othersources of ionizing radiation.

In some embodiments, the prodrugs or double prodrugs of the disclosureare administered orally at least about three hours prior to theadministration of chemotherapy. In some embodiments, the prodrugs ordouble prodrugs of the disclosure are orally administered at least about15 minutes prior to the administration of chemotherapy, such as at leastabout 5 minutes, or about 5 minutes to about 30 minutes prior to theadministration of chemotherapy. In some embodiments, the prodrugs ordouble prodrugs of the disclosure are orally administered at least about30 minutes prior to the administration of chemotherapy, such as at leastabout 15 minutes, or about 15 minutes to about 60 minutes prior to theadministration of chemotherapy. In some embodiments, the prodrugs ordouble prodrugs of the disclosure are orally administered at least about60 minutes prior to the administration of chemotherapy, such as at leastabout 30 minutes, or about 30 minutes to about 120 minutes prior to theadministration of chemotherapy. In some embodiments, the prodrugs ordouble prodrugs of the disclosure are orally administered at least about2 hours prior to the administration of chemotherapy, such as at leastabout 1 hour, or about 1 hour to about 4 hours prior to theadministration of chemotherapy. In some embodiments, the prodrugs ordouble prodrugs of the disclosure are orally administered at least about4 hours prior to the administration of chemotherapy, such as at leastabout 2 hours, or about 2 hours to about 8 hours prior to theadministration of chemotherapy. In some embodiments, the prodrugs ordouble prodrugs of the disclosure are orally administered at least about6 hours prior to the administration of chemotherapy, such as at leastabout 8 hours, or about 8 hours to about 12 hours prior to theadministration of chemotherapy.

In some embodiments, the prodrugs or double prodrugs of the disclosureare administered subcutaneously at least about three hours prior to theadministration of chemotherapy. In some embodiments, the prodrugs ordouble prodrugs of the disclosure are subcutaneously administered atleast about 15 minutes prior to the administration of chemotherapy, suchas at least about 5 minutes, or about 5 minutes to about 30 minutesprior to the administration of chemotherapy. In some embodiments, theprodrugs or double prodrugs of the disclosure are subcutaneouslyadministered at least about 30 minutes prior to the administration ofchemotherapy, such as at least about 15 minutes, or about 15 minutes toabout 60 minutes prior to the administration of chemotherapy. In someembodiments, the prodrugs or double prodrugs of the disclosure aresubcutaneously administered at least about 60 minutes prior to theadministration of chemotherapy, such as at least about 30 minutes, orabout 30 minutes to about 120 minutes prior to the administration ofchemotherapy. In some embodiments, the prodrugs or double prodrugs ofthe disclosure are subcutaneously administered at least about 2 hoursprior to the administration of chemotherapy, such as at least about 1hour, or about 1 hour to about 4 hours prior to the administration ofchemotherapy. In some embodiments, the prodrugs or double prodrugs ofthe disclosure are subcutaneously administered at least about 4 hoursprior to the administration of chemotherapy, such as at least about 2hours, or about 2 hours to about 8 hours prior to the administration ofchemotherapy. In some embodiments, the prodrugs or double prodrugs ofthe disclosure are subcutaneously administered at least about 6 hoursprior to the administration of chemotherapy, such as at least about 8hours, or about 8 hours to about 12 hours prior to the administration ofchemotherapy.

In some embodiments, the prodrugs or double prodrugs of the disclosureare administered intravenously at least about three hours prior to theadministration of chemotherapy. In some embodiments, the prodrugs ordouble prodrugs of the disclosure are intravenously administered atleast about 15 minutes prior to the administration of chemotherapy, suchas at least about 5 minutes, or about 5 minutes to about 30 minutesprior to the administration of chemotherapy. In some embodiments, the oprodrugs or double prodrugs of the disclosure are intravenouslyadministered at least about 30 minutes prior to the administration ofchemotherapy, such as at least about 15 minutes, or about 15 minutes toabout 60 minutes prior to the administration of chemotherapy. In someembodiments, the prodrugs or double prodrugs of the disclosure areintravenously administered at least about 60 minutes prior to theadministration of chemotherapy, such as at least about 30 minutes, orabout 30 minutes to about 120 minutes prior to the administration ofchemotherapy. In some embodiments, the prodrugs or double prodrugs ofthe disclosure are intravenously administered at least about 2 hoursprior to the administration of chemotherapy, such as at least about 1hour, or about 1 hour to about 4 hours prior to the administration ofchemotherapy. In some embodiments, the prodrugs or double prodrugs ofthe disclosure are intravenously administered at least about 4 hoursprior to the administration of chemotherapy, such as at least about 2hours, or about 2 hours to about 8 hours prior to the administration ofchemotherapy. In some embodiments, the prodrugs or double prodrugs ofthe disclosure are intravenously administered at least about 6 hoursprior to the administration of chemotherapy, such as at least about 8hours, or about 8 hours to about 12 hours prior to the administration ofchemotherapy.

In some embodiments, the prodrugs or double prodrugs of the disclosureare administered topically at least about three hours prior to theadministration of chemotherapy. In some embodiments, the prodrugs ordouble prodrugs of the disclosure are topically administered at leastabout 15 minutes prior to the administration of chemotherapy, such as atleast about 5 minutes, or about 5 minutes to about 30 minutes prior tothe administration of chemotherapy. In some embodiments, the prodrugs ordouble prodrugs of the disclosure are topically administered at leastabout 30 minutes prior to the administration of chemotherapy, such as atleast about 15 minutes, or about 15 minutes to about 60 minutes prior tothe administration of chemotherapy. In some embodiments, the prodrugs ordouble prodrugs of the disclosure are topically administered at leastabout 60 minutes prior to the administration of chemotherapy, such as atleast about 30 minutes, or about 30 minutes to about 120 minutes priorto the administration of chemotherapy. In some embodiments, the prodrugsor double prodrugs of the disclosure are topically administered at leastabout 2 hours prior to the administration of chemotherapy, such as atleast about 1 hour, or about 1 hour to about 4 hours prior to theadministration of chemotherapy. In some embodiments, the prodrugs ordouble prodrugs of the disclosure are topically administered at leastabout 4 hours prior to the administration of chemotherapy, such as atleast about 2 hours, or about 2 hours to about 8 hours prior to theadministration of chemotherapy. In some embodiments, the prodrugs ordouble prodrugs of the disclosure are topically administered at leastabout 6 hours prior to the administration of chemotherapy, such as atleast about 8 hours, or about 8 hours to about 12 hours prior to theadministration of chemotherapy.

In some embodiments, the prodrugs or double prodrugs of the disclosureare administered cutaneously at least about three hours prior to theadministration of chemotherapy. In some embodiments, the prodrugs ordouble prodrugs of the disclosure are cutaneously administered at leastabout 15 minutes prior to the administration of chemotherapy, such as atleast about 5 minutes, or about 5 minutes to about 30 minutes prior tothe administration of chemotherapy. In some embodiments, the prodrugs ordouble prodrugs of the disclosure are cutaneously administered at leastabout 30 minutes prior to the administration of chemotherapy, such as atleast about 15 minutes, or about 15 minutes to about 60 minutes prior tothe administration of chemotherapy. In some embodiments, the o prodrugsor double prodrugs of the disclosure are cutaneously administered atleast about 60 minutes prior to the administration of chemotherapy, suchas at least about 30 minutes, or about 30 minutes to about 120 minutesprior to the administration of chemotherapy. In some embodiments, theprodrugs or double prodrugs of the disclosure are cutaneouslyadministered at least about 2 hours prior to the administration ofchemotherapy, such as at least about 1 hour, or about 1 hour to about 4hours prior to the administration of chemotherapy. In some embodiments,the prodrugs or double prodrugs of the disclosure are cutaneouslyadministered at least about 4 hours prior to the administration ofchemotherapy, such as at least about 2 hours, or about 2 hours to about8 hours prior to the administration of chemotherapy. In someembodiments, the prodrugs or double prodrugs of the disclosure arecutaneously administered at least about 6 hours prior to theadministration of chemotherapy, such as at least about 8 hours, or about8 hours to about 12 hours prior to the administration of chemotherapy.

In some embodiments, the one or more compounds, salts or compositions ofthe disclosure are useful in reducing the potential of futurecarcinogenesis of surviving cells after exposure to ionizing radiationor chemotherapy has occurred. In some embodiments, the one or morecompounds, salts or compositions of the disclosure are administeredbefore exposure to ionizing radiation or chemotherapy. In someembodiments, the one or more compounds, salts or compositions of thedisclosure are administered simultaneously/concurrently with exposure toionizing radiation or chemotherapy. In some embodiments, the one or morecompounds, salts or compositions of the disclosure are administeredafter exposure to ionizing radiation or chemotherapy.

In some embodiments, the one or more compounds, salts or compositions ofthe disclosure are orally administered at least about 15 minutes afterradiation exposure, such as at least about 5 minutes, or about 5 minutesto about 30 minutes after radiation exposure. In some embodiments, theone or more compounds, salts or compositions of the disclosure areorally administered at least about 30 minutes after radiation exposure,such as at least about 15 minutes, or about 15 minutes to about 60minutes after radiation exposure. In some embodiments, the one or morecompounds, salts or compositions of the disclosure are orallyadministered at least about 60 minutes after radiation exposure, such asat least about 30 minutes, or about 30 minutes to about 120 minutesafter radiation exposure. In some embodiments, the one or morecompounds, salts or compositions of the disclosure are orallyadministered at least about 2 hours after radiation exposure, such as atleast about 1 hour, or about 1 hour to about 4 after radiation exposure.In some embodiments, the one or more compounds, salts or compositions ofthe disclosure are orally administered at least about 4 hours afterradiation exposure, such as at least about 2 hours, or about 2 hours toabout 8 hours after radiation exposure. In some embodiments, the one ormore compounds, salts or compositions of the disclosure are orallyadministered at least about 6 hours after radiation exposure, such as atleast about 8 hours, or about 8 hours to about 12 hours after radiationexposure.

In some embodiments, the one or more compounds, salts or compositions ofthe disclosure are administered subcutaneously at least about threehours after radiation exposure. In some embodiments, the one or morecompounds, salts or compositions of the disclosure are subcutaneouslyadministered at least about 15 minutes after radiation exposure, such asat least about 5 minutes, or about 5 minutes to about 30 minutes afterradiation exposure. In some embodiments, the one or more compounds,salts or compositions of the disclosure are subcutaneously administeredat least about 30 minutes after radiation exposure, such as at leastabout 15 minutes, or about 15 minutes to about 60 minutes afterradiation exposure. In some embodiments, the one or more compounds,salts or compositions of the disclosure are subcutaneously administeredat least about 60 minutes after radiation exposure, such as at leastabout 30 minutes, or about 30 minutes to about 120 minutes afterradiation exposure. In some embodiments, the one or more compounds,salts or compositions of the disclosure are subcutaneously administeredat least about 2 hours after radiation exposure, such as at least about1 hour, or about 1 hour to about 4 hours after radiation exposure. Insome embodiments, the one or more compounds, salts or compositions ofthe disclosure are subcutaneously administered at least about 4 hoursafter radiation exposure, such as at least about 2 hours, or about 2hours to about 8 hours after radiation exposure. In some embodiments,the one or more compounds, salts or compositions of the disclosure aresubcutaneously administered at least about 6 hours after radiationexposure, such as at least about 8 hours, or about 8 hours to about 12hours after radiation exposure.

In some embodiments, the one or more compounds, salts or compositions ofthe disclosure are administered topically at least about three hoursafter radiation exposure. In some embodiments, the one or morecompounds, salts or compositions of the disclosure are topicallyadministered at least about 15 minutes after radiation exposure, such asat least about 5 minutes, or about 5 minutes to about 30 minutes afterradiation exposure. In some embodiments, the one or more compounds,salts or compositions of the disclosure are topically administered atleast about 30 minutes after radiation exposure, such as at least about15 minutes, or about 15 minutes to about 60 minutes after radiationexposure. In some embodiments, the one or more compounds, salts orcompositions of the disclosure are topically administered at least about60 minutes after radiation exposure, such as at least about 30 minutes,or about 30 minutes to about 120 minutes after radiation exposure.

In some embodiments, the one or more compounds, salts or compositions ofthe disclosure are administered cutaneously at least about three hoursafter radiation exposure. In some embodiments, the one or morecompounds, salts or compositions of the disclosure are cutaneouslyadministered at least about 15 minutes after radiation exposure, such asat least about 5 minutes, or about 5 minutes to about 30 minutes afterradiation exposure. In some embodiments, the one or more compounds,salts or compositions of the disclosure are cutaneously administered atleast about 30 minutes after radiation exposure, such as at least about15 minutes, or about 15 minutes to about 60 minutes after radiationexposure. In some embodiments, the one or more compounds, salts orcompositions of the disclosure are cutaneously administered at leastabout 60 minutes after radiation exposure, such as at least about 30minutes, or about 30 minutes to about 120 minutes after radiationexposure.

In some embodiments, the one or more compounds, salts or compositions ofthe disclosure are administered orally at least about three hours afteradministration of chemotherapy. In some embodiments, the one or morecompounds, salts or compositions of the disclosure are orallyadministered at least about 15 minutes after administration ofchemotherapy, such as at least about 5 minutes, or about 5 minutes toabout 30 minutes after administration of chemotherapy. In someembodiments, the one or more compounds, salts or compositions of thedisclosure are orally administered at least about 30 minutes afteradministration of chemotherapy, such as at least about 15 minutes, orabout 15 minutes to about 60 minutes after administration ofchemotherapy. In some embodiments, the one or more compounds, salts orcompositions of the disclosure are orally administered at least about 60minutes after administration of chemotherapy, such as at least about 30minutes, or about 30 minutes to about 120 minutes after administrationof chemotherapy. In some embodiments, the one or more compounds, saltsor compositions of the disclosure are orally administered at least about2 hours after the administration of chemotherapy, such as at least about1 hour, or about 1 hour to about 4 hours after the administration ofchemotherapy. In some embodiments, the one or more compounds, salts orcompositions of the disclosure are orally administered at least about 4hours after the administration of chemotherapy, such as at least about 2hours, or about 2 hours to about 8 hours after the administration ofchemotherapy. In some embodiments, the one or more compounds, salts orcompositions of the disclosure are orally administered at least about 6hours after the administration of chemotherapy, such as at least about 8hours, or about 8 hours to about 12 hours after the administration ofchemotherapy.

In some embodiments, the one or more compounds, salts or compositions ofthe disclosure are administered subcutaneously at least about threehours after the administration of chemotherapy. In some embodiments, theone or more compounds, salts or compositions of the disclosure aresubcutaneously administered at least about 15 minutes after theadministration of chemotherapy, such as at least about 5 minutes, orabout 5 minutes to about 30 minutes after the administration ofchemotherapy. In some embodiments, the one or more compounds, salts orcompositions of the disclosure are subcutaneously administered at leastabout 30 minutes after the administration of chemotherapy, such as atleast about 15 minutes, or about 15 minutes to about 60 minutes afterthe administration of chemotherapy. In some embodiments, the one or morecompounds, salts or compositions of the disclosure are subcutaneouslyadministered at least about 60 minutes after the administration ofchemotherapy, such as at least about 30 minutes, or about 30 minutes toabout 120 minutes after the administration of chemotherapy. In someembodiments, the one or more compounds, salts or compositions of thedisclosure are subcutaneously administered at least about 2 hours afterthe administration of chemotherapy, such as at least about 1 hour, orabout 1 hour to about 4 hours after the administration of chemotherapy.In some embodiments, the one or more compounds, salts or compositions ofthe disclosure are subcutaneously administered at least about 4 afterthe administration of chemotherapy, such as at least about 2 hours, orabout 2 hours to about 8 hours after the administration of chemotherapy.In some embodiments, the one or more compounds, salts or compositions ofthe disclosure are subcutaneously administered at least about 6 hoursafter the administration of chemotherapy, such as at least about 8hours, or about 8 hours to about 12 hours after the administration ofchemotherapy.

In some embodiments, the one or more compounds, salts or compositions ofthe disclosure are administered topically at least about three hoursafter the administration of chemotherapy. In some embodiments, the oneor more compounds, salts or compositions of the disclosure are topicallyadministered at least about 15 minutes after the administration ofchemotherapy, such as at least about 5 minutes, or about 5 minutes toabout 30 minutes after the administration of chemotherapy. In someembodiments, the one or more compounds, salts or compositions of thedisclosure are topically administered at least about 30 minutes afterthe administration of chemotherapy, such as at least about 15 minutes,or about 15 minutes to about 60 minutes after the administration ofchemotherapy. In some embodiments, the one or more compounds, salts orcompositions of the disclosure are topically administered at least about60 minutes after the administration of chemotherapy, such as at leastabout 30 minutes, or about 30 minutes to about 120 minutes after theadministration of chemotherapy. In some embodiments, the one or morecompounds, salts or compositions of the disclosure are topicallyadministered at least about 2 hours after the administration ofchemotherapy, such as at least about 1 hour, or about 1 hour to about 4hours after the administration of chemotherapy. In some embodiments, theone or more compounds, salts or compositions of the disclosure aretopically administered at least about 4 after the administration ofchemotherapy, such as at least about 2 hours, or about 2 hours to about8 hours after the administration of chemotherapy. In some embodiments,the one or more compounds, salts or compositions of the disclosure aretopically administered at least about 6 hours after the administrationof chemotherapy, such as at least about 8 hours, or about 8 hours toabout 12 hours after the administration of chemotherapy.

In some embodiments, the one or more compounds, salts or compositions ofthe disclosure are administered cutaneously at least about three hoursafter the administration of chemotherapy. In some embodiments, the oneor more compounds, salts or compositions of the disclosure arecutaneously administered at least about 15 minutes after theadministration of chemotherapy, such as at least about 5 minutes, orabout 5 minutes to about 30 minutes after the administration ofchemotherapy. In some embodiments, the one or more compounds, salts orcompositions of the disclosure are cutaneously administered at leastabout 30 minutes after the administration of chemotherapy, such as atleast about 15 minutes, or about 15 minutes to about 60 minutes afterthe administration of chemotherapy. In some embodiments, the one or morecompounds, salts or compositions of the disclosure are cutaneouslyadministered at least about 60 minutes after the administration ofchemotherapy, such as at least about 30 minutes, or about 30 minutes toabout 120 minutes after the administration of chemotherapy. In someembodiments, the one or more compounds, salts or compositions of thedisclosure are cutaneously administered at least about 2 hours after theadministration of chemotherapy, such as at least about 1 hour, or about1 hour to about 4 hours after the administration of chemotherapy. Insome embodiments, the one or more compounds, salts or compositions ofthe disclosure are cutaneously administered at least about 4 after theadministration of chemotherapy, such as at least about 2 hours, or about2 hours to about 8 hours after the administration of chemotherapy. Insome embodiments, the one or more compounds, salts or compositions ofthe disclosure are cutaneously administered at least about 6 hours afterthe administration of chemotherapy, such as at least about 8 hours, orabout 8 hours to about 12 hours after the administration ofchemotherapy.

In some embodiments, one or more compounds, salts or compositions of thedisclosure are useful as radioprotectants against the toxicities ofionizing radiation. In some embodiments, the amount of one or morecompounds, salts of the disclosure is about 10 mg to about 10,000 mg. Incertain such embodiments, the amount is at least about 500 mg, such asabout 500 mg to 1500 mg, administered orally. In certain suchembodiments, one or more compounds, salts or compositions of thedisclosure are administered as two or more oral doses depending on theamount and duration of radiation exposure. In some embodiments, theamount of one or more compounds of the disclosure useful asradioprotectants is at least about 500 mg, such as about 500 mg to about1500 mg, administered subcutaneously. In certain such embodiments, oneor more compounds, salts or compositions of the disclosure areadministered as two subcutaneous injections. In some embodiments, acirculating concentration of one or more compounds of the disclosure(and/or and a metabolite thereof) of about 2 μM to about 100 μM iseffective as a radioprotectant. In certain such embodiments, theconcentration of one or more compounds of the disclosure is about 5 μMto about 50 μM. Alternatively, or in addition to, a tissue concentrationof one or more compounds of the disclosure (and/or a metabolite thereof)of about 4 μM to about 700 μM is effective as a radioprotectant. Incertain such embodiments, the effective tissue concentration is about 20μM to about 350 μM.

In some embodiments, one or more compounds, salts or compositions of thedisclosure are useful in treating the toxicities associated ionizingradiation, especially in subjectswith head and neck cancer. In certainsuch embodiments, oral, subcutaneous or intravenous administrationreduces side effects. In certain such embodiments, oral administrationreduces side effects. In some embodiments, subcutaneous administrationreduces side effects. In certain such embodiments, intravenousadministration reduces side effects. In some embodiments, subcutaneousadministration reduces side effects.

In some embodiments, one or more compounds, salts or compositions of thedisclosure are useful as chemoprotectants against the toxicities ofchemotherapy. In some embodiments, the amount of one or more compoundsor salts of the disclosure is about 10 mg to about 10,000 mg. In certainsuch embodiments, the amount is at least about 500 mg, such as about 500mg to about 1500 mg, administered orally. In certain such embodiments,one or more compounds, salts or compositions of the disclosure areadministered as two oral doses. In some embodiments, the amount of oneor more compounds or salts of the disclosure useful as chemoprotectantsis at least about 500 mg, such as about 500 mg to about 1500 mg,administered subcutaneously. In certain such embodiments, one or morecompounds, salts or compositions of the disclosure are administered astwo subcutaneous injections. In some embodiments, a circulatingconcentration of one or more compounds of the disclosure (and/or and ametabolite thereof) of about 2 μM to about 100 μM is effective as achemoprotectant. In certain such embodiments, the concentration of oneor more compounds of the disclosure is about 5 μM to about 50 μM.Alternatively, or in addition to, a tissue concentration of one or morecompounds of the disclosure (and/or a metabolite thereof) of about 4 μMto about 700 μM is effective as a chemoprotectant. In certain suchembodiments, the effective tissue concentration is about 20 μM to about350 μM.

In some embodiments, one or more compounds, salts or compositions of thedisclosure are useful in treating the toxicities associated withchemotherapy, especially in subjects with head and neck cancer. Incertain such embodiments, oral or subcutaneous administration reducesside effects. In certain such embodiments, oral administration reducesside effects. In some embodiments, subcutaneous administration reducesside effects.

In some embodiments, one or more compounds, salts or compositions of thedisclosure are useful in treating diseases requiring bone marrow growth,such as MDS, or in promoting recovery of bone marrow function. Incertain such embodiments, a circulating concentration of one or morecompounds of the disclosure (and/or a metabolite thereof) of about 2 μMto about 100 μM is effective. Alternatively, or in addition, a tissueconcentration of one or more compounds of the disclosure (and/or ametabolite thereof) of about 0.1 μM to about 1000 μM is effective, suchas about 10 μM to about 500 μM.

In some embodiments, usual subject doses for administration of one ormore compounds or salts of the disclosure usually range from about 10mg/day to about 10,000 mg/day. In some embodiments, the doses range fromabout 50 mg/day to about 6000 mg/day, about 100 mg/day to about 4000mg/day, about 200 mg/day to about 3500 mg/day, about 50 mg/day to about1000 mg/day, about 100 mg/day to about 900 mg/day, about 50 mg/day toabout 1500 mg/day, about 100 mg/day to about 1000 mg/day, about 200mg/day to about 750 mg/day, about 50 mg/day to about 1200 mg/day, about100 mg/day to about 1100 mg/day, about 200 mg/day to about 1000 mg/day,or about 200 mg/day to about 800 mg/day.

Stated in terms of subject body weight, in some embodiments usualdosages range from about 0.5 mg/kg/day to about 16 mg/kg/day, about 1.1mg/kg/day to about 15 mg/kg/day, about 0.6 mg/kg/day to about 100mg/kg/day, about 1.1 mg/kg/day to about 66 mg/kg/day, about 2.2mg/kg/day to about 58 mg/kg/day, about 0.5 mg/kg/day to about 25mg/kg/day, about 1 mg/kg/day to about 16 mg/kg/day, about 3.3 mg/kg/dayto about 12.5 mg/kg/day, about 0.5 mg/kg/day to about 20 mg/kg/day,about 1.1 mg/kg/day to about 18 mg/kg/day, about 2.2 mg/kg/day to about16.2 mg/kg/day, or about 2.2 mg/kg/day to about 13.5 mg/kg/day.

Stated in terms of subject body surface areas, usual dosages range fromabout 22 mg/m²/day to about 666 mg/m²/day, about 45 mg/m²/day to about600 mg/m²/day, about 23 mg/m²/day to about 4000 mg/m²/day, about 45mg/m²/day to about 2666 mg/m²/day, about 90 mg/m²/day to about 2333mg/m²/day, about 22 mg/m²/day to about 1000 mg/m²/day, about 45mg/m²/day to about 666 mg/m²/day, about 133 mg/m²/day to about 500mg/m²/day, about 22 mg/m²/day to about 800 mg/m²/day, about 45 mg/m²/dayto about 720 mg/m²/day, about 90 mg/m²/day to about 650 mg/m²/day, orabout 90 mg/m²/day to about 540 mg/m²/day.

In some embodiments, the one or more compounds, salts or compositions ofthe disclosure are administered orally. In certain such embodiments,usual subject doses for oral administration of one or more compounds orsalts of the disclosure usually range from about 50 mg/day to about 6000mg/day, commonly from about 100 mg/day to about 4000 mg/day, andtypically from about 200 mg/day to about 3500 mg/day. Stated in terms ofsubject body weight, usual dosages range from about 0.6 mg/kg/day toabout 100 mg/kg/day, commonly from about 1.1 mg/kg/day to about 66mg/kg/day, and typically from about 2.2 mg/kg/day to about 58 mg/kg/day.Stated in terms of subject body surface areas, usual dosages range fromabout 23 mg/m²/day to about 4000 mg/m²/day, commonly from about 45mg/m²/day to about 2666 mg/m²/day, and typically from about 90 mg/m²/dayto about 2333 mg/m²/day.

In some embodiments, the one or more compounds, salts or compositions ofthe disclosure are administered subcutaneously. In certain suchembodiments, subject doses for subcutaneous administration of one ormore compounds or salts of the disclosure usually range from about 50mg/day to about 1500 mg/day, commonly from about 100 mg/day to about1000 mg/day and typically from about 200 mg/day to about 750 mg/day.Stated in terms of body weight, usual dosages range from about 0.5mg/kg/day to about 25 mg/kg/day, commonly from about 1 mg/kg/day toabout 16 mg/kg/day and typically from about 3.3 mg/kg/day to about 12.5mg/kg/day. Stated in terms of subject body surface areas, usual dosesrange from about 22 mg/m²/day to about 1000 mg/m²/day, commonly fromabout 45 mg/m²/day to about 666 mg/m²/day and typically from about 133mg/m²/day to about 500 mg/m²/day.

In some embodiments when the one or more compounds, salts orcompositions of the disclosure are administered subcutaneously, subjectdoses for subcutaneous administration of one or more compounds or saltsof the disclosure usually range from about 50 mg/day to about 1200mg/day, commonly from about 100 mg/day to about 1100 mg/day andtypically from about 200 mg/day to about 1000 mg/day. Stated in terms ofbody weight, usual dosages range from about 0.5 mg/kg/day to about 20mg/kg/day, commonly from about 1.1 mg/kg/day to about 18 mg/kg/day andtypically from about 2.2 mg/kg/day to about 16.2 mg/kg/day. Stated interms of subject body surface areas, usual doses range from about 22mg/m²/day to about 800 mg/m²/day, commonly from about 45 mg/m²/day toabout 720 mg/m²/day and typically from about 90 mg/m²/day to about 650mg/m²/day.

In some embodiments for parenteral administration by injection (e.g., byintramuscular, subcutaneous and intravenous injections, bolus injectionor continuous infusion), one or more compounds, salts or compositions ofthe disclosure can be administered by continuous infusion subcutaneouslyover a period of 15 minutes to 24 hours.

For other modes of administration, dosage amount and interval can beadjusted individually to provide effective plasma and/or tissue levelsof one or more compounds or salts of the disclosure, and/or a metabolitethereof, according to the pharmacokinetic profiles described herein, aspreviously described.

The actual amount of one or more compounds, salts or compositions of thedisclosure administered will, of course, be dependent on the subjectbeing treated, the condition being treated, the subject's weight, theseverity of the affliction, the mode of administration and the judgmentof the prescribing physician.

Methods and Uses of Treatment

One aspect of this disclosure is a method of treating or preventing atoxicity or condition associated with ionizing radiation exposure orchemotherapy in a subject in need thereof, comprising administering tosaid subject a therapeutically effective amount of a compound accordingto this disclosure, or a pharmaceutically acceptable salt, solvate,hydrate, polymorph or combination thereof or a hydrate, solvate orpolymorph of the salt, or of a pharmaceutical composition according tothis disclosure.

In some embodiments, the toxicity is one or more of bone marrowtoxicity, central nervous system toxicity, immunological toxicity,gastrointestinal toxicity, neurotoxicity, nephrotoxicity, ototoxicity,cardiotoxicity, hepatoxicity, cutaneous toxicity, alopecia mucositis,xerostomia, infertility, peripheral neuropathy, pulmonary toxicity orrenal failure. In some embodiments the toxicity is an acute radiationtoxicity. In some embodiments the toxicity is a late radiation toxicity(i.e., late onset toxicity). Ionizing radiation causes injury to cellsand tissues. Damaged cells continue to function normally until they diewhile attempting to undergo mitosis. Accordingly, symptoms of ionizingradiation injury occur more rapidly for organs with rapid cellturnovers. Conversely, symptoms of ionizing radiation injury for organswith a slower turnover rate occur after a latency period. Symptomsassociated with acute radiation toxicity can occur within hours, days orweeks, such as within 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week,2 weeks or 3 weeks after of the incident radiation exposure. Symptomsassociated with late radiation toxicity can occur within several monthsor years, such as 2 months, 3 months, 4 months, 5 months, 6 months, 7months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3years, or 4 years after the incident ionizing radiation exposure.

In some embodiments, one or more compounds, salts or compositions ofthis disclosure are useful in the treatment of Acute Radiation Syndrome(ARS), often referred to as radiation sickness. In humans, exposure tohigh doses of acute penetrating radiation can lead to the development ofARS. Depending on the radiation dose and extent of exposure, ARS canmanifest as bone marrow syndrome, gastrointestinal syndrome, andcardiovascular (CV)/central nervous system (CNS) syndrome. ARS has threedistinct stages—the prodromal phase, the latent asymptomatic phase, andthe overt systemic illness phase. In some embodiments, one or morecompounds, salts or compositions of this disclosure are useful in thetreatment of the prodromal phase of ARS. In some embodiments, one ormore compounds, salts or compositions of this disclosure are useful inthe treatment of the latent asymptomatic phase of ARS. In someembodiments, one or more compounds, salts or compositions of thisdisclosure are useful in the treatment of the overt systemic illnessphase of ARS.

In some embodiments, the one or more compounds, salts or compositions ofthis disclosure are useful in preventing, eliminating or alleviating oneor more symptoms of ARS. In some embodiments, the one or more compounds,salts or compositions of this disclosure are useful in preventing,eliminating or alleviating one or more symptoms of ARS during theprodromal phase of ARS. In some embodiments, symptoms of ARS in theprodromal phase include, but are not limited to, nausea, vomiting,headache, diarrhea, loss of appetite, fatigue, fever, skin damage andhair loss.

In some embodiments, one or more compounds, salts or compositions areuseful at preventing, eliminating or slowing the development of theovert systemic illness phase of ARS when administered during the latentphase of ARS.

In some embodiments, one or more compounds, salts or compositions ofthis disclosure are useful in preventing, eliminating or alleviating oneor more symptoms of ARS during the overt systemic illness phase of ARS.In some embodiments, the overt systemic illness phase of ARS isassociated with one or more of bone marrow syndrome, gastrointestinalsyndrome or cardiovascular syndrome. The symptoms of bone marrowsyndrome include, but are not limited to, anorexia, fever, malaise, dropin blood cell counts, infection and hemorrhage. In some embodiments, theovert systemic illness phase of ARS is associated with gastrointestinalsyndrome. The symptoms of gastrointestinal syndrome include, but are notlimited to malaise, anorexia, diarrhea, fever, dehydration, electrolyteimbalance, and infection. In some embodiments, the overt systemicillness phase of ARS is associated with cardiovascular syndrome. Thesymptoms associated with cardiovascular syndrome include, but are notlimited to, diarrhea, convulsions and coma.

In some embodiments, the one or more compounds, salts or compositions ofthis disclosure are useful in the treatment of a toxicity or conditionassociated with acute radiation exposure. In some embodiments, the oneor more compounds, salts or compositions of this disclosure are usefulin the treatment of a toxicity or condition associated with chronicradiation exposure. Acute radiation exposure is short-term, high-levelexposure that can occur from events such as a nuclear power plantaccident, nuclear warfare, detonation of an explosive device thatdisperses radioactive material (dirty bomb), detonation of a nuclearweapon, the detonation of a small radioactive device, or space travel.Chronic radiation exposure is long-term, low-level exposure which canoccur through events, such as, airplane travel, space travel,installation and/or decommissioning of nuclear reactors of naval vesselsor land-based nuclear reactors, exposure to naturally occurringradioactive materials in the soil, water and vegetation, or exposure tosmall doses over time in the workplace such as, for example, medicalprofessionals working with X-ray machines or researchers working withradioactive reagents, or regions contaminated by nuclear reactoraccidents or terrorist attacks.

Astronauts are vulnerable to the enhanced levels of radiation present inouter space. Galactic cosmic rays are characterized by highly energeticand fully ionized nuclei. The charged particles within galactic cosmicrays are more damaging than terrestrial sources of radiation, and canlead to the development of, inter alia, severe and progressive cognitivedefects and the development of neurological disorders such as prematureaging, Alzheimer's disease and dementia (Parihar, V. K., ete al., “Whathappens to your brain on the way to Mars”, Sci. Adv., 2015, no. 4,e1400256, DOI: 10.1126/sciadv.1400256; and Cucinotta, F. A., et al.,“Space radiation risks to the central nervous system”, Life Sciences inSpace Research, 2014, 2, 54-69). Another source of radiation exposurefor astronauts is from the Sun in the form of solar flares or coronalmass ejections. Coronal mass ejections release large quantities ofenergetic protons and electromagnetic radiation. In some embodiments,one or more compounds, salts or compositions of this disclosure areuseful in preventing, eliminating or reducing the development ofcognitive disorders associated with exposure to ionizing radiation. Insome embodiments, the ionizing radiation is one or more of galacticcosmic rays, chronic solar radiation, solar flares or coronal massejections. In some embodiments, the cognitive disorder is Alzheimer'sdisease or dementia. In some embodiments, one or more compounds, saltsor compositions of this disclosure are useful in preventing, eliminatingor reducing premature aging associated with exposure to ionizingradiation.

In some embodiments, one or more compounds, salts or compositions ofthis disclosure are useful in the treatment of individuals such asfirst-responders, nuclear power plant workers, pilots, flightattendants, and astronauts that have been exposed to high doses ofradiation, acute and/or chronic, in the occupational setting. In someembodiments, one or more compounds, salts or compositions of thedisclosure are useful in the treatment of emergency personnel such aspolicemen, firefighters, and military members that have been exposed toradiation while responding to an attack or accident involvingradioactive material.

In some embodiments, one or more compounds, salts or compositions of thedisclosure are useful in reducing the risk of tumor induction in asubject who has been exposed to, is being exposed to, or will be exposedto ionizing radiation. In some embodiments, the source of the ionizingradiation is nuclear warfare, a nuclear reactor, air travel, spacetravel, or radiation therapy. In one or more embodiments, one or morecompounds, salts or compositions of the disclosure are administered to asubject in need thereof, before the subject has been exposed to ionizingradiation. In one or more embodiments, one or more compounds, salts orcompositions of the disclosure are administered to a subject in needthereof, while the subject is being exposed to ionizing radiation. Inone or more embodiments, one or more compounds, salts or compositions ofthe disclosure are administered to a subject in need thereof, after thesubject has been exposed to ionizing radiation.

In some embodiments, the one or more compounds, salts or compositions ofthe disclosure are useful in reducing the risk of the development ofcancer in a subject who has been exposed to, is being exposed to, orwill be exposed to ionizing radiation. In some embodiments, the canceris leukemia, lymphoma, rectal or colorectal cancer, breast cancer,prostate cancer, androgen-dependent prostate cancer, lung cancer,mesothelioma, head and neck cancer, esophageal cancer, gastric cancer,pancreatic cancer, gastrointestinal cancer, renal cell cancer,testicular cancer, ovarian cancer, germ cell cancer, glioma or any otherprimary, solid tumor or liquid tumor.

In some embodiments, one or more compounds, salts or compositions of thedisclosure are useful in the treatment of subjects with cancer who arebeing treated, has been treated or will be treated with ionizingradiation or chemotherapy. In some embodiments, the cancer is ahematological cancer. In some embodiments, the cancer is bone cancer. Insome embodiments, the cancer is leukemia. In some embodiments, thecancer is lymphoma, rectal or colorectal cancer, breast cancer, prostatecancer, androgen-dependent prostate cancer, lung cancer, mesothelioma,head and neck cancer, esophageal cancer, gastric cancer, pancreaticcancer, gastrointestinal cancer, renal cell cancer, testicular cancer,ovarian cancer, germ cell cancer, glioma or any other primary or solidtumor. In other embodiments, the subject suffers from a bone marrowdisorder. In some embodiments, the subject has head and neck cancer.

In some embodiments, one or more compounds, salts or compositions of thedisclosure are useful in treating or preventing a toxicity or conditionassociated with ionizing radiation in a subject with cancer who is alsobeing treated with radiotherapy. In some embodiments, the radiotherapyis selected from gamma radiation, X-radiation, proton beam radiation,electron beam radiation or gamma radiation from cobalt-60 decay. In someembodiments, the radiotherapy is in the form of a radiopharmaceutical.In some embodiments, the radiopharmaceutical is selected fromstrontium-89, samarium-153 or radium-223.

In some embodiments, one or more compounds, salts or compositions of thedisclosure are useful in reducing the risk of secondary tumor inductionin a subject being treated with radiotherapy or chemotherapy. In someembodiments, one or more compounds, salts or compositions of thedisclosure are useful in reducing the risk of secondary tumor inductionin a subject being treated with radiotherapy. In some embodiments, oneor more compounds, salts or compositions of the disclosure are useful inreducing the risk of secondary tumor induction in a subject beingtreated with chemotherapy.

In some embodiments, one or more compounds, salts or compositions of thedisclosure are useful in treating or preventing a toxicity or conditionassociated with ionizing radiation in a subject with cancer who is alsobeing treated with chemotherapy. In some embodiments, the chemotherapyis selected from the group consisting of cyclophosphamide, ifosfamide,etoposide, oxaliplatin, cisplatin, carboplatin, mechlorethamine,melphalan, chlorambucil, cyclophosphamide, streptozocin, carmustine,lomustine, bleomycin, busulfan, dacarbazine, doxorubicin, daunoubicin,temozolomide, thiotepa, altretamine, procarbaine, hexamethylmelamine,teniposide and mitoxantrone.

In another aspect, the one or more compounds, salts or compositionsdescribed herein are useful in selectively protecting normal tissuesagainst the toxicities associated with ionizing radiation orchemotherapy. In some embodiments, one or more compounds, salts orcompositions described herein are able to selectively protect normaltissues against the toxicities associated with ionizing radiation orchemotherapy with minimal adverse effects on the tumor response. Withoutwishing to be bound by theory, the ability of the phosphorylatedprodrugs and double prodrugs of the disclosure to be metabolized to theactive thiol form will be enhanced in healthy tissues as opposed totumor tissues. This is due to the higher presence of alkalinephosphatase in healthy tissues versus tumor tissues. Therefore, thephosphorylated prodrugs and double prodrugs of the disclosure will beconverted to their active thiol counterparts in healthy tissues to agreater extent than in tumor tissues, thus, protecting healthy tissuesselectively over tumor tissues.

One or more compounds, salts or compositions described herein can beadministered to cancer subjects receiving radiation therapy orchemotherapy. In some embodiments, administering one or more compounds,salts or compositions of the disclosure is useful in protecting thesubjects against the toxicities or conditions associated with theexposure to the therapy. Such toxicities include, but are not limitedto, bone marrow toxicity, central nervous system toxicity, immunologicaltoxicity, neurotoxicity, nephrotoxicity, ototoxicity, cardiotoxicity,alopecia, peripheral neuropathy and mucositis. In some embodiments, thetoxicities include xerostomia, infertility, pulmonary toxicity, andrenal failure. In some embodiments, one or more compounds, salts orcompositions described herein are able to protect tissues from thegenotoxic and carcinogenic effects of radiation and certain forms ofchemotherapy. In some embodiments, one or more compounds, salts orcompositions described herein are able to protect tissues fromradiation-induced fibrosis.

In some embodiments, one or more compounds, salts or compositions of thedisclosure is useful as a cytoprotectant administered to cancer subjectsin conjunction with therapeutic radiation or chemotherapy to amelioratethe harmful effects of ionizing radiation or chemotherapeutic agents tonormal tissues.

In some embodiments, one or more compounds, salts or compositions of thedisclosure are useful as a chemoprotectant administered to cancersubjects in conjunction with chemotherapy to ameliorate the harmfuleffects of chemotherapeutic agents to normal tissues. In someembodiments, one or more compounds, salts or compositions of thedisclosure are administered separately (before or after), sequentiallyor concurrently with a chemotherapeutic agent selected from the groupconsisting of cyclophosphamide, ifosfamide, etoposide, oxaliplatin,cisplatin, carboplatin, mechlorethamine, melphalan, chlorambucil,cyclophosphamide, streptozocin, carmustine, lomustine, bleomycin,busulfan, dacarbazine, doxorubicin, daunoubicin, temozolomide, thiotepa,altretamine, procarbaine, hexamethylmelamine, teniposide andmitoxantrone.

In some embodiments, one or more compounds, salts or compositions of thedisclosure are useful as a radioprotectant administered to cancersubjects in conjunction with therapeutic radiation to ameliorate theharmful effects of ionizing radiation to normal tissues. In someembodiments, one or more compounds, salts or compositions of thedisclosure are administered separately (before or after), sequentiallyor concurrently with radiotherapy, wherein the radiotherapy is selectedfrom the group consisting of gamma radiation, X-radiation, proton beamradiation, electron beam radiation or gamma radiation from cobalt-60decay. In some embodiments, one or more compounds or compositions of thedisclosure are administered sequentially or concurrently with aradiopharmaceutical. In some embodiments, the radiopharmaceutical isselected from strontium-89, samarium-153 or radium-223.

In some embodiments, the subject being treated with one or morecompounds, salts or compositions of the disclosure is a cancer subject .In some embodiments, the cancer is a hematological cancer. In someembodiments, the cancer is bone cancer. In some embodiments, the canceris leukemia. In some embodiments, the cancer is lymphoma, rectal orcolorectal cancer, breast cancer, prostate cancer, androgen-dependentprostate cancer, lung cancer, mesothelioma, head and neck cancer,esophageal cancer, gastric cancer, pancreatic cancer, gastrointestinalcancer, renal cell cancer, testicular cancer, ovarian cancer, germ cellcancer, glioma or any other primary or solid tumor. In otherembodiments, the subject suffers from a bone marrow disorder. In someembodiments, the subject has head and neck cancer.

In some embodiments, the subject being treated with one or morecompounds, salts or compositions of the disclosure is a cancer subjectbeing treated with a chemotherapeutic agent, radiotherapy or both. Insome embodiments, chemotherapeutic agent, radiotherapy or both arefurther combined with immunotherapy. In some embodiments theimmunotherapy is selected from the group consisting of immune checkpointinhibitors, T-cell transfer therapy, monoclonal antibodies, treatmentvaccines and immune system modulators.

In some embodiments, one or more compounds, salts or compositions of thedisclosure are useful in treating subjects suffering from diseasesrequiring bone marrow growth, such as myelodysplastic syndromes (MDS).In some embodiments, one or more compounds or compositions of thedisclosure are useful in treating subjects in need of more rapidrecovery of bone marrow function following chemotherapy. In someembodiments, one or more compounds, salts or compositions of thedisclosure are useful in stimulating bone marrow production or function.In some embodiments, one or more compounds, salts or compositions of thedisclosure are useful in preventing the development of or alleviatingthe existing symptoms of bone marrow dysfunction or prolonging thesurvival of the subject being treated.

In some embodiments, one or more compounds, salts or compositions of thedisclosure are useful for treating or preventing radiation-inducedcognitive impairment. Radiation-induced cognitive impairment has beenreported to occur in up to 50-90% of adult cancer subjects with braintumor who survive more than 6 months after undergoing whole-brainirradiation. Radiation-induced cognitive impairment is driven byoxidative stress and inflammatory responses. (Greene-Schloesser, D.;Robbins, M. E., “Radiation-induced cognitive impairment-from bench tobedside”, Neuro. Oncol. 2012, 14, iv37-iv44). Without wishing to bebound by theory, treatment with a ROS scavenger will reduce the damagingeffects caused by radiation-induced oxidative stress, and will preventor alleviate the development of cognitive impairment in a subject thathas been, will be or is being exposed to ionizing radiation.

In some embodiments, one or more compounds, salts or compositions of thedisclosure are useful in the treatment of diseases or conditionsassociated with oxidative stress. Oxidative stress is caused by animbalance between ROS and antioxidants, and can lead to the developmentof renal ischemia reperfusion injury, myocardial ischemia, spinal cordischemia and reperfusion injury, ventilator induced lung injury,methotrexate-induced hepatoxicity, acute lung injury, Alzheimer'sdisease, Parkinson's disease, rheumatoid arthritis, myocardialinfarction, cardiovascular disease, septic shock, chronic inflammation,Friedreich ataxia, Leber's hereditary optic neuropathy, myoclonusepilepsy, ragged red fiber disease, Mitochondrial Encephalopathy, LacticAcidosis and Stroke (MELAS), COVID-19-associated cytokine storm,COVID-19-associated multisystem inflammatory syndrome in children(MIS-C), or post-COVID-19 SARS-CoV-2-induced autoimmunity (see Uttara etal., Oxidative Stress and Neurodegenerative Diseases: A Review ofUpstream and Downstream Antioxidant Therapeutic Options, CurrentNeuropharmacology, 2009, Vol. 7, pp 65-74; Akbulut, S, et al,Cytoprotective effects of amifostine, ascorbic acid and N-acetylcystineagainst methotrexate-induced hepatoxicity in rats, World J.Gastroenterol, 2014, Vol. 20(9), pp 10158-10165; Fu, P., et al,Amifostine reduces lung vascular permeability via suppression ofinflammatory signaling, Eur. Respir. J, 2009, Vol. 33(3), pp 612-624;Chronidou, F., et al, Beneficial effect of the oxygen free radicalscavenger amifostine (WR-2721) on spinal cord ischemia/reperfusioninjury in rabbits, Thorac. Cardiovasc. Surg., 2009, Vol. 4(50), doi:10.1186/1749-8090-4-50; Chok, M. K., et al, Renoprotective potency ofamifostine in rat renal ischaemia-reprfusion, Nephro Dial Translplant,2010, Vol 25, pp 3845-3851; and Wu, S., et al, Amifostine PretreatmentAttenuates Myocardial Ischemia/Reperfusion Injury by InhibitingApoptosis and Oxidative Stress, Oxid. Med. Cell. Longev., 2017, doi:10.1155/2017/4130824). Without wishing to be bound by theory, thecompounds, salts and compositions of the disclosure reduce the adverseeffects associated with oxidative stress caused by ROS.

In some embodiments, one or more compounds, salts or compositions of thedisclosure are useful for slowing the rate of the aging process in asubject. Without wishing to be bound by theory, the accumulation of freeradical damage to cells over time contributes to the aging process. Thecompounds, salts or compositions of the disclosure are useful as ROSscavengers and reduce the amount of damage to cells caused by ROS overtime. This reduction in ROS associated cell damage slows the overallrate of aging and improves the health span of the subject.

In some embodiments, one or more compounds, salts or compositions of thedisclosure are useful for treating or preventing COVID-19-associatedcytokine storm, COVID-19-associated multisystem inflammatory syndrome inchildren (MIS-C), and post-COVID-19 SARS-CoV-2-induced autoimmunity. Insome embodiments, one or more compounds, salts or compositions of thedisclosure are useful for treating or preventing COVID-19-associatedcytokine storm. In some embodiments, one or more compounds, salts orcompositions of the disclosure are useful for treating or preventingCOVID-19-associated multisystem inflammatory syndrome in children(MIS-C). In some embodiments, one or more compounds, salts orcompositions of the disclosure are useful for treating or preventingpost-COVID-19 SARS-CoV-2-induced autoimmunity.

Animal and Cell Models

For any compound, salt or composition described herein, thetherapeutically effective or protective amount can be initiallyestimated from cell culture assays. In some embodiments, one or morecompounds, salts or compositions of the disclosure can be used asresearch reagents and delivered to animals to understand bioactivity,enzymatic activity, gene expression, interactions with other molecules,and impacts on animal physiology in healthy or diseased animals orcells. In some embodiments, healthy or diseased cells are contacted withone or more compounds, salts or compositions of the disclosure. In someembodiments, one or more compounds, salts or compositions of thedisclosure can be formulated in animal models to achieve a circulatingconcentration range of compound, and/or a metabolite thereof, thatincludes an effective concentration as determined in cell culture. Suchinformation can be used to more accurately determine useful doses inhumans (Washburn, L C., Rafter, J J., and Hayes, R L (1976). Predictionof the Effective Radioprotective Dose of WR-2721 in Humans Through anInterspecies Tissue Distribution Study. Radiat. Res. 66:100-105).

In some embodiments, therapeutically or protective effective amounts ofthe compounds, salts or compositions of the disclosure for use in humanscan also be estimated from animal models. For example, animal models canbe used to develop a dose response curve that can be used to determinean effective or protective circulating concentration of the compoundsand/or metabolites described herein. Based on those studies, a dose forhumans can be formulated that achieves an efficacious circulatingconcentration.

Equivalents

The foregoing description and following examples detail certain specificembodiments of the disclosure and describe the best mode contemplated bythe inventors. It will be appreciated, however, that no matter howdetailed the foregoing may appear in text, the disclosure may bepracticed in many ways and the disclosure should be construed inaccordance with the appended claims and any equivalents thereof.

Although the disclosed teachings have been described with reference tovarious applications, methods, compounds, salts, and compositions, itwill be appreciated that various changes and modifications can be madewithout departing from the teachings herein. The following examples areprovided to better illustrate the disclosed teachings and are notintended to limit the scope of the teachings presented herein. While thepresent teachings have been described in terms of these exemplaryembodiments, the skilled artisan will readily understand that numerousvariations and modifications of these exemplary embodiments are possiblewithout undue experimentation. All such variations and modifications arewithin the scope of the current teachings.

Incorporation by Reference

All references cited herein, including patents, patent applications,papers, text books, and the like, and the references cited therein, tothe extent that they are not already, are hereby incorporated byreference in their entirety. In the event that one or more of theincorporated literature and similar materials differs from orcontradicts this application, including but not limited to definedterms, term usage, described techniques, or the like, this applicationcontrols.

EXAMPLES

The following examples illustrate the synthesis of various compounds andsalts according to the present disclosure. The skilled worker willreadily appreciate that the following examples are merely illustrativeand can be modified according to methods and techniques commonly knownin the art.

One skilled in the art will recognize that in some cases, the compoundsdescribed herein can exist as a mixture of diastereomers and/orenantiomers. The skilled worker will also appreciate that such isomersmay be separated at various stages of their synthesis using conventionaltechniques, or a combination of such techniques, such as, but notlimited to, crystallization, normal phase chromatography, reverse phasechromatography, and chiral chromatography, to afford single enantiomersof the compounds described herein.

Example 1: Synthesis of di-tent-butyl(2-(mercaptomethyl)propane-1,3-diyl)bis (methylcarbamate) (PrC-210-Boc2)

Intermediate PrC-210-Boc2 is synthesized according to Scheme 5. Doublechloride displacement from 3-chloro-2-(chloromethyl)prop-1-ene with twoequivalents of N-methyl mesitylene-sulfonamide followed byhydroboration-oxidation generates the corresponding sulfonamide alcohol.The alcohol is converted to a sulfonate ester upon addition of mesylchloride to the reaction mixture. Subsequent treatment with thioaceticacid followed by deprotection of the amine under acidic conditionsgenerates the deprotected thioate derivative. The tert-butoxycarbonyl(Boc) protected compound (PrC-210-Boc2) is then synthesized upontreatment with di-tert-butyl decarbonate. For exemplary reactionconditions, see Copp, R. R.; Peebles, D. D.; Fahl, W. E., Bioorg. Med.Chem. Lett., 2011, Vol. 21(24), pp 7426-7430; and US2014/107216.

Example 2: Synthesis of intermediate di-tent-butyl(2-((phosphonothio)methyl)propane-1,3-diyl)bis(methylcarbamate)(Prc-210-PT-Boc2)

Intermediate PrC-210-PT-Boc2 is synthesized according to the proceduresummarized in Scheme 6. Phosphorylation of PrC-210-Boc2 is afforded upontreatment with bis(9H-fluoren-9-ylmethyl)-diisopropylamidophosphitefollowed by oxidation with t-butyl hydroperoxide. Subsequentdeprotection under basic conditions affords intermediatePrC-210-PT-Boc2. For exemplary reaction conditions, see Dorfmueller, H.C.; Borodkin, V. S.; Blair, D. E.; Pathak, S; Navratilova, I.; VanAalten, D. M. F.; Amino Acids, 2011, Vol. 40, pp 781-792.

Example 3: Synthesis of compound1—{[3-(methylamino)-2-[(methylamino)methyl]propyl]sulfanyl} phosphonicacid (PrC-210-PT)

Compound 1 is synthesized as depicted in Scheme 7. Double chloridedisplacement from 3-chloro-2-(chloromethyl)prop-1-ene with twoequivalents of N-methyl mesitylene-sulfonamide followed by hydroborationfurnishes the corresponding sulfonamide alcohol. The alcohol isconverted to the corresponding bromide upon treatment withtriphenylphosphine dibromide. Subsequent addition of lithiumthiophosphate affords compound 1 (PrC-210-PT). For exemplary reactionconditions see Laval, J. D.; Roman V.; Laduranty, J.; Miginiac, L.;Lion, C.; et al., Eur. J. Med. Chem., 1993, Vol. 28 (9), pp 709-714;Carrol, F. I.; Gopinathan, M. B.; Philip, A., J. Med. Chem. 1990, Vol.33(9), pp 2501-2508; Copp, R. R.; Peebles, D. D.; Fahl, W. E., Bioorg.Med. Chem. Lett., 2011, Vol. 21(24), pp 7426-7430; Moene, W.; Vos, M.;Schakel, M.; De Kanter, F. J. J; Schmitz, R. F.; Klumpp, G. W., Eur. J.Chem., 2000, Vol 6(2), pp 225-236.

Compound 13 is synthesized in an analogous manner to compound 1 usingN-ethyl-2,4,6-trimethylbenzenesulfonamide as a starting material.

Example 4: Alternative Synthesis of Compound 1

The synthesis of compound 1 is alternatively accomplished as depicted byScheme 8. The PrC-210-thioacetate derivative is synthesized as shown inScheme 5. Subsequent treatment with di-tent-butyl decarbonate affordsthe N-Boc protected thioester. Hydrolysis of the thioester upon theaddition of NaOH to the reaction mixture affords the corresponding N-Bocprotected thiol. S-phosphorylation of the thiol is achieved by theaddition of bis(9H-fluoren-9-ylmethyl)-diisopropylamidophosphitefollowed by oxidation with t-butyl hydroperoxide. Deprotection of theamine with trifluoroacetic acid followed by deprotection of thephosphonate under basic conditions furnishes compound 1 (PrC-210-PT).For exemplary reaction conditions see Dorfmueller, H. C.; Borodkin, V.S.; Blair, D. E.; Pathak, S; Navratilova, I.; Van Aalten, D. M. F.;Amino Acids, 2011, Vol. 40, pp 781-792.

Example 5: Alternative Synthesis of PrC-210-PT

Compound 1 is alternatively synthesized according to Scheme 9.Intermediate PrC-210-PT-Boc2 is synthesized as shown in Scheme 6.Subsequent deprotection upon treatment with trifluoro acetic acidaffords PrC-210-PT (compound 1). For exemplary reaction conditions, seeWO2019/34866 A1.

Example 6: Synthesis of Compound2—({[(benzoyloxy)methoxy]({[3-(methylamino)-2-[(methylamino)methyl]propyl]sulfanyl})phosphoryl}oxy)methyl benzoate (PrC-210-PT-BzOM)

Compound 2 is synthesized according to Scheme 10. IntermediatePrC-210-PT-Boc2 is synthesized according to Scheme 6. Subsequenttreatment with acyloxymethyl chloride followed by Boc deprotectionaffords compound 2 (PrC-210-PT-BzOM). For exemplary reaction conditions,see Ponaire, S., et al., Eur. J. Med. Chem., 2012, Vol. 51, pp.

277-285 and W02009/69100.

Example 7: Synthesis of Compound3—1-[({1-[(2,2-dimethylpropanoyl)oxy]ethoxy}({[3-(methylamino)-2-[(methylamino)methyl]propyl]sulfanyl})phosphoryl)oxy]ethyl 2,2-dimethylpropanoate(PrC-210-PT-POE)

Compound 3 is synthesized as shown in Scheme 11. IntermediatePrC-210-PT-Boc2 is synthesized according to Scheme 6. Subsequenttreatment with 1-chloroethyl pivalate followed by Boc deprotectionaffords compound 3 (PrC-210-PT-POE). For exemplary reaction conditionssee WO2009/69100 and CN108948084.

Example 8: Synthesis of Compound 4: -bis{4-[(2,2-dimethylpropanoyl)sulfanyl]butyl}{[3-(methylamino)-2-[(methylamino)methyl]propyl]sulfanyl}phosphonate(PrC-210-PT-PivTB)

Compound 4 is synthesized as shown in Scheme 12. Nucleophilicsubstitution of 4-bromobutan-1-ol with 2,2-dimethylpropanethioic S-acidaffords S-(4-hydroxybutyl) 2,2-dimethylpropanethioate. Addition of1,1-dichloro-N,N-diisopropylphosphanamine to the reaction mixtureaffords 5,S′-((((diisopropylamino)phosphanediyl)bis(oxy))bis(butane-4,1-diyl))bis(2,2-dimethylpropanethioate).

Intermediate PrC-210-Boc2 is synthesized according to Scheme 5.PrC-210-Boc2 is phosphorylated in the presence of tetrazole upontreatment with S,S′-((((diisopropylamino)phosphanediyl)bis(oxy))bis(butane-4,1-diyl)) bis(2,2-dimethylpropanethioate) followedby oxidation with t-butyl hydroperoxide. Boc deprotection under acidicconditions affords compound 4 (PrC-210-PT-PivTB). For exemplary reactionconditions, see Egron,et. al., Nucleosides and Nucleotides, 1998, Vol.17, pp 1725-1729, and Knapp, S., et al., J. Org. Chem., 2002, 67(9), pp2995-2999.

Compound 12 (PrC-210-PT-PivTP) is synthesized in an analogous manner tocompound 4 (PrC-210-PivTB) using the appropriate starting materials.

Example 9: Synthesis of Compound 5:bis{4-[(2,2-dimethylpropanoyl)sulfanyl]butyl}{[3-(methylamino)-2-[(methylamino)methyl]propyl]sulfanyl}phosphonate(PrC-210-PT-POCE)

Compound 5 is synthesized according to Scheme 13. IntermediatePrC-210-PT-Boc2 is synthesized according to Scheme 6. Subsequenttreatment with 1-chloroethyl propyl carbonate followed by Bocdeprotection affords PrC-210-PT-POCE. For exemplary reaction conditionssee US2017/233429 and CN108948084.

Example 10: Synthesis of Compound 6:bis{4-[(2,2-dimethylpropanoyl)sulfanyl]butyl}{[3-(methylamino)-2-[(methylamino)methyl]propyl]sulfanyl}phosphonate(PrC-210-PT-POC)

Compound 6 is synthesized as shown in Scheme 14. IntermediatePrC-210-PT-Boc2 is synthesized according to Scheme 6. Subsequenttreatment with chloromethyl isopropyl carbonate followed by Bocdeprotection affords compound 6 (PrC-210-PT-POCE). For exemplaryreaction conditions, see Majer, et al., J. Med. Chem., 2016, 59, pp2810-2819, and CN108948084.

Example 11: Synthesis of Compound 7:4-(3-chlorophenyl)-2-{[3-(methylamino)-2-[(methylamino)methyl]propyl]sulfanyl}-1,3,215-dioxaphosphinan-2-one(PrC-210-PT-ClDOxP)

Compound 7 is synthesized as shown in Scheme 15. An Aldol additionbetween 3-chlorobenzaldehyde and ethyl acetate in the presence oflithium di-iso-propyl amine (LDA) affords ethyl3-(3-chlorophenyl)-3-hydroxypropanoate. Subsequent reduction withlithium aluminum hydride followed by treatment with1,1-dichloro-N,N-diisopropylphosphanamine results in the corresponding1,3,2-dioxaphosphinane derivative.

Intermediate PrC-210-Boc2 is prepared according to Scheme 5.PrC-210-Boc2 is phosphorylated upon treatment of with the1,3,2-dioxaphosphinane derivative followed by oxidation with t-butylhydroperoxide. Subsequent Boc deprotection under acidic conditionsaffords compound 7 (PrC-210-PT-C1DOxP). For exemplary reactionconditions, see Erion, et al., JACS, 2004, 126, pp 5154-5163 and Knapp,S., et al, J. Org. Chem., 2002, 67(9), pp 2995-2999.

Example 12: Synthesis of Compound 8:2-{[3-(methylamino)-2-[(methylamino)methyl]propyl]sulfanyl}-4-(2-methylpyridin-3-yl)-1,3,215-dioxaphosphinan-2-one (PrC-210-PT-PyDOxP)

Compound 8 is synthesized as shown in Scheme 16. An Aldol additionreaction between pyridine-3-carboxaldehyde and ethyl acetate in thepresence of lithium di-iso-propyl amine (LDA) affords ethyl3-hydroxy-3-(2-methylpyridin-3-yl)propanoate. Subsequent reduction withlithium aluminum hydride produces the corresponding diol. The diol isnext reacted with 2,2-dimethoxypropane to furnish the isopropylidenederivative. Treatment with n-butyl lithium to selectively deprotonatethe 2-position using the ortho-directing activity of the 1,3-dioxanering and reaction with bromomethane affords intermediate 11-a.

Intermediate 11-a is next converted to the corresponding diol underacidic conditions. Subsequent addition of phosphoryl chloride furnishesthe dioxaphosphinane derivative. Subsequent Boc deprotection affordscompound 8. For exemplary reaction conditions, see Tsukada, et al,Bioorganic and Medicinal Chemistry Letters, 2010, 20, pp 2938-2941 andEliel, et al, J. Am. Chem. Soc., 1986, pp 6651.

Example 13: Synthesis of Appropriate Starting Materials for Compounds 9,10 and 11 (PrC-210-PT-PivTB2, Prc-210-PT-PivTB3 and Prc-210-PT-PivTB4)

3-methylbutan-2-one is refluxed with paraformaldehyde to afford4-hydroxy-3,3-dimethylbutan-2-one. Subsequent bromination followed bynucleophilic substitution upon treatment with 2,2-dimethylpropanethioicS-acid in the presence of triethylamine furnishes the correspondingthioate (PivTB2). For exemplary reaction conditions, see Kiuru, E.;Ahmed, Z.; Lönnberg, H.; Beigelman, L.; Ora, M, J. Org. Chem., 2012,Vol. 78(3), p. 950-959.

Bromination of ethyl 2-methyl-3-oxobutanoate followed by nucleophilicsubstitution with thioacetic acid furnishes the correspondingthioanhydride. Reflux of the thioanhydride with paraformaldehyde affordsthe alcohol (PivTB3). For exemplary reaction conditions, see Kiuru, E.;Ahmed, Z.; Lönnberg, H.; Beigelman, L.; Ora, M, J. Org. Chem., 2012,Vol. 78(3), p. 950-959.

Nucleophilic substitution of ethyl 4-chloro-3-oxobutanoate with2,2-dimethylpropanethioic S-acid affords the corresponding thioatederivative. Reflux of the thioate derivative with paraformaldehyde inthe presence of triethyl amine furnishes the diol intermediate.Subsequent Johnson-Claisen rearrangement upon treatment of the diol with1,1,1-triethoxyethane generates the precursor (PivTB4). For exemplaryreaction conditions, see Kiuru, E.; Loennberg, H.; Ora, M. Helb. Chim.,2013, Vol. 96(11), p. 1997-2008 and US2008/125483.

Example 14: Synthesis of Compound 9:{4-[(2,2-dimethylpropanoyl)sulfanyl]-2,2-dimethyl-3-oxobutoxy}({[3-(methylamino)-2-[(methylamino)methyl]propyl]sulfanyl})phosphinicacid (PrC-210-PivTB2)

Compound 9 (PrC-210-PivTB2) is prepared according to Scheme 20.Treatment the appropriate precursor (PivTB2, Example 13) with3-((chloro(diisopropylamino) phosphaneyl)oxy)propanenitrile affords thecorresponding phosphane derivative. Subsequent treatment of PrC-210-Boc2(Scheme 5) with the phosphane derivative followed by oxidation withtent-butyl hydroperoxide furnishes intermediate 9-a. Cyanoethyldeprotection with triethylamine followed by Boc deprotection withanhydrous trifluoroacetic acid affords compound 9. For exemplaryreaction conditions, see Romanucci, V., et al., Bioorg. Med. Chem. 2014,Vol. 22(3), pp. 960-966; Kulesza, A., Frank, C.G.; Aebi, M.; Vasella,A., Helv. Chim., 2004, Vol. 87(12), pp. 3106-3118; Bazin, H. G.; Bess,L. S.; Livesay, M. T.; Mwakwari, S. C.; Johnson, D. A., TetrahedronLett., 2016, Vol. 57(19), pp. 2063-2066; and U.S. Pat. No. 6,949,528 B1

Compounds 10 and 11 will be synthesized in an analogous manner tocompound 9 using the appropriate precursors, i.e., PivTB3 and PivTB4(Example 13).

Example 15: Synthesis of compound 14:1-{[(1-{[2-(2-methoxyethoxy)acetyl]oxy}ethoxy)({[3-(methylamino)-2-[(methylamino)methyl]propyl]sulfanyl})phosphoryl]oxy}ethyl2-(2-methoxyethoxy)acetate (PrC-210-PT-PEGOE1)

Compound 14 (PrC-210-PT-PEGOE1) is prepared according to Scheme 21.Treatment of 2-(2-methoxyethoxy)acetyl chloride with acetaldehyde in thepresence of ZnCl₂ affords 1-chloroethyl 2-(2-methoxyethoxy)acetate.Alkylation of the phosphate hydroxy groups of PrC-210-PT-Boc2 (Scheme 6)is achieved via addition of triethyl amine to a dry DMF solution of1-chloroethyl 2-(2-methoxyethoxy)acetate and PrC-210-PT-Boc2 (Scheme 6).The reaction mixture is allowed to stir at 70° C. for 4 hours.Subsequent Boc deprotection with anhydrous HCl furnishes compound 14.For exemplary reaction conditions, see Nudelman et al., Eur. J. Med.Chem., 2001, vol. 36, #1, pp. 63 - 74.

Compound 15 ({[3 -(methylamino)-2- [(methylamino)methyl]propyl]sulfanyl}[1-(2,5,8,11-tetraoxatetradecanoyloxy)ethoxy]phosphinic acid)(PrC-210-PT-PEGOE2) is synthesized in a manner similar to compound 14.However, 2,5,8,11-tetraoxatetradecan-14-oyl chloride will be used inplace of 2-(2-methoxyethoxy)acetyl chloride to make 1-chloroethyl2,5,8,11-tetraoxatetradecan-14-oate, and 1 equivalent of 1-chloroethyl2,5,8,11-tetraoxatetradecan-14-oate in solution will be added dropwiseto a solution of PrC-210-PT-Boc2 to alkylate only 1 of the phosphatehydroxyl groups, using an appropriate aprotic organic solvent such asTHF.

Example 16: Synthesis of Compound 16{[3-(methylamino)-2-[(methylamino)methyl]propyl]sulfanyl}[1-(2,5,8,11,14-pentaoxaicosanoyloxy)ethoxy]phosphinicacid (PrC-210-PT-PEGOE3)

Compound 16 is synthesized according to Scheme 22. Nucleophilicsubstitution of 1-chloroethyl carbonochloridate with3,6,9,12-tetraoxaoctadecan-1-ol provides the PEG precursor,1-chloroethyl (3,6,9,12-tetraoxaoctadecyl) carbonate. Dropwise additionof a solution containing only 1 equivalent of the PEG precursortoPrC-210-PT-Boc2 (Scheme 6) will serve to alkylate only 1 of thephosphate hydroxyl groups, resulting in the Boc protected derivative ofcompound 16. Subsequent Boc deprotection under acidic conditions affordscompound 16. For exemplary reaction conditions, see US 2008/0125483.

Example 17: Synthesis of Compound 18 propan-2-yl(2S)-2-[((R+S)-{[3-(methylamino)-2-[(methylamino)methyl]propyl]sulfanyl}(phenoxy)phosphoryl)amino]propanoate(S, R+S-PrC-210-PT-alaf)

Double prodrug S, R+S-PrC-210-PT-alaf (compound 18) is preparedaccording to Scheme 24. Conversion of phosphoryl chloride to thecorresponding aryl ester is afforded upon treatment with phenol.Addition of L-Alanine isopropyl ester hydrochloride and triethylamine tothe reaction mixture affords the alafenamide derivative. Subsequenttreatment with PrC-210-Boc2 (see Scheme 5) in the presence of1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) generates the Boc protectedanalogue of (S, R+S)-PrC-210-PT-alaf. Subsequent Boc deprotectionfurnishes compound 18. For exemplary reaction conditions, seeUS2014/248242 and WO2016/41877.

To isolate the pure diastereomers of 18, (S,S)-PrC-210-PT-alaf and(S,R)-PrC-210-PT-alaf, the Boc protected analogue of the mixture ofdiastereomers (S, R+S)-PrC-210-PT-alaf is purified by recrystallizationor silica gel chromatography to yield Boc protected analogs of (S,S)-PrC-210-PT-alaf and (S, R)-PrC-210-PT-alaf. Each of these could bedeprotected with anhydrous TFA to yield the pure (S, S)- and (S,R)-diastereomers of 18. Alternately, the two diastereomers (S,R+S)-PrC-210-PT-alaf could be separated by fractional recrystallizationof salts of appropriate chiral anions or dianions such as the dibenzoyltartrate salt followed by neutralization to yield the pure (S, S)- and(S, R)-diastereomers of 18.

Example 18: Synthesis of2,2-dimethyl-1-{[3-(methylamino)-2-[(methylamino)methyl]propyl]sulfanyl}propan-1-one(compound 19, S-acyl-PrC-210)

Compound 19 is prepared according to Scheme 25. Double chloridedisplacement from 3-chloro-2-(chloromethyl)prop-1-ene with twoequivalents of N-methyl mesitylene-sulfonamide followed byhydroboration-oxidation generates the corresponding sulfonamide alcohol.Mesylation of the alcohol upon addition of mesyl chloride to thereaction mixture followed by treatment with lithium2,2-dimethylpropanethioate affords the S-acyl derivative. Subsequentremoval of the mesitylene protecting groups under acidic conditionsresults in the hydrobromide salt form of S-acyl-PrC-210. Other saltforms can be made from the hydrobromide using anion exchange resin.Alternately, the free base 19 can be made using careful treatment with 2equivalents of aqueous KOH, added dropwise at 5° C. The base can beconverted to more stable salts by treatment with the appropriate acid.For exemplary reaction conditions see Copp, R. R.; Peebles, D. D.; Fahl,W. E., Bioorg. Med. Chem. Lett., 2011, Vol. 21(24), pp 7426-7430.

Example 19: Synthesis of Compound 20 ethyl4-(benzoylthio)-2-(((hydroxy((3-(methylamino)-2-((methylamino)methyl)propyl)thio)phosphoryl)oxy)methyl)-2-methyl-3-oxobutanoate(PrC-210-PT-BzTB1)

Compound 20 is synthesized according to Scheme 25. Bromination of ethyl2-methyl-3-ketobutyrate upon addition of Br₂ in a DCM solution affordsthe corresponding bromide. Substitution of the bromide upon treatmentwith benzenecarbothioc S-acid in the presence of triethylamine affordsthe benzoylthioester derivative. Hydroxymethylation upon treatment ofthe bonzoylthioester with formaldehyde in the presence of triethylaminein dioxane affords the hydroxyl intermediate. Subsequent treatment withdiphenylphosphite in pyridine at 20° C. for lh followed by treatmentwith triethylamine and pyridine in water at 0° C. affords intermediate20-a. For Exemplary reaction conditions see Kiuru, E.; Ahmed, Z.;Lönnberg, H.; Beigelman, L.; Ora, M, J. Org. Chem., 2012, Vol. 78(3), p.950-959; and Chevolot et al., Angew., 2007, Vol. 46, pp 2398-2402.

To a THF solution of PrC-210-Boc2 (Scheme 5),1,2-di(pyridine-2-yl)disulfane is added to afford the disulfidederivative. After work up, the disulfide is dissolved in dry THF. Thephosphinic acid (20-a) and N,O-bis(trimethylsilyl)trifluoroacetamide aredissolved in a separate dry THF solution, followed by subsequentaddition to the disulfide solution. The reaction mixture is stirredunder reflux for 3 to 5 hours. Subsequent Boc deprotection usingtrifluoroacetic acid affords compound 20. For exemplary reactionconditions, see Dugave, C., Kessler, P., Tetrahedron Lett., 1994, Vol.35, #51, pp 9557-9560.

Compound 17 is synthesized via an analogous procedure to that ofcompound 20 using the appropriate starting materials. In particular2-methoxy-2′-ethoxy-2″-ethoxy-ethyl 2-methyl-3-ketobutyrate in place ofethyl 2-methyl-3-ketobutyrate in step a, and 2-dimethylpropanethioicS-acid in place of benzenecarbothioic S-acid in step b.

Example 20: Synthesis of (2-(piperazin-2-yl)propane-2-thiol) (Compound21, 2Pip-2PrSH)

Compound 21 is synthesized according to Scheme 26. Ring closure of2-amino ((4-methoxybenzyl)thio)-3-methylbutanoic acid upon treatmentwith phosgene generates the oxazole-dione derivative. Subsequenttreatment with glycine methyl ester hydrochloride under basic conditionsfollowed by reflux affords the piperazinedione derivative. PMB(p-methoxybenzyl) deprotection followed by reduction with lithiumaluminum hydride affords compound 21. For exemplary reaction conditions,see Richter, L. S.; Gadek, T. R., Tetrahedron: Asymmetry, 1996, Vol.7(2), pp 427-434.

Example 21: Synthesis of ((1,4-diazepan-6-yl)methanethiol HBr) (Compound22 HBr, DzCH2SH)

Compound 22 is prepared according to Scheme 27. Halogen exchange of3-chloro-2-(chloromethyl)prop-1-ene upon treatment with sodium iodide inacetone affords 3-iodo-2-iodomethylpropene. Cyclization ofN,N′-(ethane-1,2-diyl)bis(4-methylbenzenesulfonamide) upon treatmentwith 3-iodo-2-iodomethylpropene to give the corresponding olefin,followed by hydroboration-oxidation generates the correspondingsulfonamide alcohol. Mesylation of the alcohol upon addition ofmethanesulfonyl chloride to the reaction mixture followed by treatmentwith sodium thioacetate affords the S-acyl derivative. Subsequentremoval of the mesitylene protecting groups under acidic conditionsresults in the hydrobromide salt form of compound 22. Treatment of thesalt with a base, such as sodium hydroxide affords the compound 22 asthe free base. For exemplary reaction conditions, see Copp, R. R.;Peebles, D. D.; Fahl, W. E., Bioorg. Med. Chem. Lett., 2011, Vol.21(24), pp 7426-7430; Matsumoto, K.; Tomioka, K., Chem. Pharm. Bull.2001, Vol 49(12), pp 1653-1657.

Example 22: Synthesis of2-methyl-4-(methylamino)-3-((methylamino)methyl)butane-2-thiol (Compound23, DM-PrC-210)

Compound 23 is prepared according to Scheme 28. Treatment of dimethylisopropylidenemalonate with hydrogen sulfide affords the thiol analogue.Subsequent addition of 4-methoxybenzyl chloride results in formation ofthe PMB protected derivative. The diol is next formed upon reductionwith lithium aluminum hydride. Conversion of the diol to the diamine isafforded by conversion of the diol to the tosylate followed by treatmentwith sodium azide and subsequent reduction with LAH. Carboxylation withacetic formic anhydride followed by reduction LAH and subsequent PMBdeprotection under acidic conditions affords DM-PrC-210. For exemplaryreaction conditions, see Foldi, Z., Kollonitsch, J., J. Chem. Sci, 1948,pp 1683-1685; Cullen W. R., Hall, L. D., Price, J. T., Spendjian, G.,Can. J. Chem., 1975, Vol. 53(3), pp 366-372; and Richter, L. S.; Gadek,T. R., Tetrahedron: Asymmetry, 1996, Vol. 7(2), pp 427-434.

Example 23: Alternative Synthesis of2-methyl-4-(methylamino)-3-((methylamino)methyl)butane-2-thiol (Compound23, DM-PrC-210)

Compound 23 is prepared according to Scheme 29. Treatment of dimethylisopropylidenemalonate with hydrogen sulfide affords the thiol analogue.Subsequent addition of 4-methoxybenzyl chloride results in formation ofthe PMB protected derivative. Treatment with NaOH followed by additionof thionyl chloride results in the chlorinated derivative. Substitutionwith methylamine affords the corresponding amide. Reduction with LAH andsubsequent PMB deprotection under acidic conditions affords DM-PrC-210.For exemplary reaction conditions see Földi, Z., Kollonitsch, J., J.Chem. Sci, 1948, pp 1683-1685; Walli, A., Dechert, S., Meyer, F., Eur.J. Org. Chem., 2013, No. 31, pp 7044-7049; and Richter, L. S.; Gadek, T.R., Tetrahedron: Asymmetry, 1996, Vol. 7(2), pp 427-434.

Example 24: Protection of DNA from Radiation-Induced Damage

The radioprotective efficacy of the thiol-containing compounds of thisdisclosure, as well as the thiol derivatives of the prodrugs and doubleprodrugs of this disclosure, is assessed in vitro. The ability of thecompounds to suppress X-ray induced DNA damage in normal human cells canbe determined using a H2AX-immunofluorescense microscopy technique todetect γ-H2AX-foci. The detection of γ-H2AX-foci is indicative of DNAdamage and is recognized as a biomarker for radiation-induceddouble-strand breaks (DSBs). See for example, Brand, M., Sommer, M.,Jermusek, F., Fahl, W. E., Uder, M., Biology Open, 2018, 7, bio035113.doi:10.1242/bio.035113.

The thiols of this disclosure (SH), and the thiol derivatives of thepro-drugs and double pro-drugs of this disclosure (PD-SH) are comparedto PrC-210, as well as to a control sample (containing no additive). Abaseline measurement of γ-H2AX-foci for each sample is determined priorto exposure to radiation and prior to the addition of the testcompounds. The efficacy of each compound is assessed at varyingconcentrations of 1, 10, 25, 50, 75 and 100 mM. The blood samples areincubated with the test compounds for 4 hrs, 3 hrs, 2 hrs, 1 hr, 30 minor 15 min before the sample is exposed to radiation. Each concentrationat each incubation time period is assessed for efficacy in reducingradiation-induced DNA damage after exposure to 10 mGy, 50 mGy or 100 mGyradiation. Some samples are exposed to radiation 10 min, 15 min, 30 minor 1 hr prior to the addition of a test compound to the sample.

The blood samples are layered into 6 mL of lymphocyte separation mediumand centrifuged. The separated lymphocytes are stained and incubatedovernight using an antibody against γ-H2AX. Fluorescence analyses areperformed, and the γ-H2AX-foci are counted. The amount of γ-H2AX-fociinduced by radiation exposure is determined by subtracting the baselinevalue of γ-H2AX-foci from the measurement. The test compounds (SH andPD-SH) are found to be useful in reducing radiation-induced DNA damage.

Example 25: Protection of Mice from Lethal Radiation

The radioprotective efficacy of the thiols, prodrugs and double prodrugsaccording to this disclosure is assessed in mice. The compounds of thedisclosure are administered via oral gavage to mice, and are compared tomice that have been administered3-(methylamino)-2-(methylaminomethyl)propane-1-thiol (PrC-210), as wellas to a control group or mice that are administered vehicle (i.e.,containing no radioprotective additive).

More specifically, mice are assigned to three groups (Groups 1, 2 and3). A control group, Group 1, is treated via oral gavage with vehicle(Lactated Ringer's and 5% dextrose, adjusted to pH 7.3 with sodiumbicarbonate) 15-90 minutes prior to a dose of 8 Gy (LD₁₀₀) radiation.Group 2 is treated via oral gavage with PrC-210, as a positive control,dissolved in Lactated Ringer's at a dose of 200 mg/kg 15-90 minutesprior to irradiation with 8 Gy (LD₁₀₀). Group 3 is treated via oralgavage with compound 1 (PrC-210-PT) dissolved in Lactated Ringer's at adose of 308 mg/kg 15-90 minutes prior to irradiation with 8 Gy (LD₁₀₀).The mortality of the three groups is assessed for 60 days postirradiation. The experiment is repeated with doses of PrC-210 rangingfrom 200 mg/kg to 450 mg/kg. Molar equivalent dosages of the testcompound (compound 1, Prc-210-PT) to PrC-210 are also assessed.

The experiment is repeated to assess the efficacy of compounds 2-23 asradioprotectors. The control group demonstrates a reduced rate ofsurvival compared to the mice treated with PrC-210 and the thiols,prodrugs and double prodrugs according to the disclosure (i.e.,compounds 1-23).

Example 26: Reduction of LD50 in Mice

The affect of the compounds according to the disclosure on the dose ofradiation required to kill 50% of mice (LD₅₀) is assessed.

Mice are assigned to three groups (Groups 1, 2 and 3). A control group,Group 1, is treated via oral gavage with vehicle (Lactated Ringer's and5% dextrose, adjusted to pH 7.3 with sodium bicarbonate) 60 minutesprior to whole body irradiation (2 Gy). Group 2 is treated via oralgavage with PrC-210, as a positive control, dissolved in LactatedRinger's at a dose of 200 mg/kg 60 minutes prior to whole bodyirradiaton (2 Gy). Group 3 is treated via oral gavage with compound 1(PrC-210-PT) dissolved in Lactated Ringer's at a dose of 308 mg/kg 60minutes prior to whole body irradiation (2 Gy). The mortality of thethree groups is assessed for 30 days post irradiation.

The experiment is repeated using varying radiation doses of 4, 6, 8, 10and 12 Gy. The LD₅₀ for each group was determined.

The experiment is repeated to assess compounds 2-23 as radioprotectors.The control group demonstrates a lower LD₅₀ compared to the mice treatedwith PrC-210 and the mice treated with the thiols, prodrugs and doubleprodrugs according to the disclosure (i.e., compounds 1-23).

Example 27. Efficacy and Maximum Tolerated Dose of PrC-210, DzCH2SH and2Pip-2PrSH in Mice

Male mice were randomized and assessed in two phases: 1) for maximumtolerated doses (MTDs) of PrC-210, DzCH2SH, and 2Pip-2PrSH to determinedose levels for the efficacy study and 2) to evaluate the efficacy ofthe compounds when administered 60±5 minutes prior to exposure to totalbody irradiation (TBI) at an LD_(100/30) dose (990 cGy) (Tables 1 and2).

For Phase 1 or 2, sterile water (vehicle), PrC-210, DzCH2SH, and2Pip2PrSH were administered at 10 mL/kg calculated based on the mostrecent body weight via oral gavage. Animals were not fasted prior toadministration of the compounds or vehicle. Mice in Phase 1 wereadministered the dose on Day 1 and mice in Phase 2 were administered thedose 60±5 minutes prior to TBI on Day 0.

Irradiation was administered once to the whole body. TBI of mice wereperformed using a 6 MV LINAC photon source (TrueBeam STx source).Animals were irradiated at a dose rate of up to 80 cGy/min to themidline of the animals. The source irradiated animals to 50% of the dosefrom anterior-posterior direction and complete irradiation from theposterior-anterior direction. Dose measurements were performed with aPTW 31010 0.1 cc Semiflex Ion chamber.

All surviving animals were observed once daily for clinical signs (e.g.,unusually low or high activity, lethargy, shivering, appearance of fur,bloody and water stool, and other symptoms of moribundity) at 1-2 hourspost-irradiation and/or post-dose and once daily on non-dosing daysuntil Day 4 (Phase 1) or Day 30 (Phase 2). The mortality rate wasassessed at 8-days post-irradiation (Table 2), which show efficaciouseffects of DzCH2SH to protect mice after irradiation.

In Phase 1 (Table 1), all animals were normal when observed and all bodyweights were within normal range. The dose level of 1000 mg/kg wasselected for Phase 2.

In Phase 2 (Table 2), survival curves of mice treated with vehicle,PrC-210, DzCH2SH or 2Pip-PrSH prior to TBI with 9.9 Gy were measured(FIG. 1 ). Mice administered with vehicle before TBI 9.9 Gy (Group 13)did not survive until Day 30. Five mice were moribund sacrificed, and 6mice were found dead. Survival in the Group 13 animals was 0% and mediansurvival time was 8 days. In mice administered with PrC-210 before TBI(Group 14), 4 animals survived until scheduled sacrifice (Day 30) while7 mice were moribund sacrificed. Survival in the Group 14 mice was 36.4%and median survival time was 11 days. The survival in the Group 14 micewas statistically significantly higher when compared to the Group 13mice by Log-rank (Mantel-Cox) (p<0.001) and Chi-square tests (p<0.05).In mice administered with DzCH2SH before TBI (Group 15), 3 animalssurvived until scheduled sacrifice (Day 30) while 7 mice were moribundsacrificed, and one mouse was found dead. Survival in the Group 15 micewas 27.3% and median survival time was 11 days. The survival in theGroup 15 mice was statistically significantly higher when compared tothe Group 13 mice by Log-rank (Mantel-Cox) test (p<0.001). In miceadministered with 2Pip-2PrSH before TBI at 9.9 Gy (Group 16), no animalssurvived until scheduled sacrifice (Day 30). Five mice were moribundsacrificed and six mice were found dead. Survival in the Group 16 micewas 0% and median survival time was 10 days. The survival in the Group16 mice was statistically significantly higher when compared to theGroup 13 mice by Log-rank (Mantel-Cox) test (p<0.02) and was notstatistically significantly different when compared by Chi-square test(p>0.05).

Rough coat, hunched posture, decreased activity and eye closed wereobserved in most mice in all groups. Eye discharge was seen in oneanimal each in Groups 13, 14 and 16, and in 2 animals in Group 15.Lethargy and swollen head were observed in one mouse each in Groups 15and 16. Hypoactivity was seen 3 animals in Group 13 and in 5 animalseach in Groups 14, 15 and 16. Tremor was seen in 4 mice in Group 14.Labored breathing was observed in one mouse in Group 15. Cold to touchskin was seen in one animal each in Groups 13 and 15, and in 4 mice inGroup 16. Swollen eye was seen in one animal in Groups 13, 14 and 16,and in 2 mice in Group 15, while sunken eye and eye cloudy were observedin 1 and 2 animals, respectively, in Group 15. Eye opacity was seen inone mouse each in Groups 13 and 15.

There were no statistically significant differences in body weightsbetween the vehicle group (Group 13) and the test article-dosed groups(Groups 14 - 16) although the mean body weight in the Group 14 animalswas higher than body weights in the Groups 13, 15 and 16 on Day 9. Itwas confirmed by body weight gain which was significantly higher inGroup 14 on Days 5 to 9 when compared to the vehicle group (Group 13).Animals in Groups 13, 15 and 16 did not gain body weights over the Days5 to 9 period.

At the highest tested dose (1,000 mg/kg), PrC-210, DzCH2SH and2Pip-2PrSH did not produce any toxicity. Mice treated PrC-210 or DzCH2SHprior to total body irradiation (LD_(100/30)) was performed, increasedsurvival of animals through 30 days post exposure. Survival beyond 30days was not assessed.

TABLE 1 Phase 1 Dose Groups for MTD determination Dose Group Number DoseVolume Concentration Number of Animals Compound (mg/kg) (mL/kg) (mg/mL)1 3 PrC-210 30 10 3 2 3 PrC-210 100 10 10 3 3 PrC-210 300 10 30 4 3PrC-210 1,000 10 100 5 3 DzCH2SH 30 10 3 6 3 DzCH2SH 100 10 10 7 3DzCH2SH 300 10 30 8 3 DzCH2SH 1,000 10 100 9 3 2Pip-2PrSH 30 10 3 10 32Pip-2PrSH 100 10 10 11 3 2Pip-2PrSH 300 10 30 12 3 2Pip-2PrSH 1,000 10100

TABLE 2 Phase 2 Dose Groups for Efficacy study Dose Group Number DoseVolume Concentration Number of Animals Compound (mg/kg) (mL/kg) (mg/mL)13 11 Vehicle 0 10 0 14 11 PrC-210 1000 10 100 15 11 DzCH2SH 1000 10 10016 11 2Pip-2PrSH 1000 10 100

Example 28. Efficacy of PrC-210 and DzCH2SH in Irradiated Mice

The efficacy of PrC-210 and DzCH2SH is evaluated in male miceadministered with the compounds 60±10 minutes prior to exposure to totalbody irradiation (TBI) at a range of radiation levels of LD_(20/30),LD_(40/30), LD_(60/30), LD_(80/30), and LD_(100/30) (Table 3). Sterilewater (vehicle), PrC-210 and DzCH2SH are administered by oral gavage at10 mL/kg calculated based on the most recent body weight. Animals arenot fasted prior to administration. After 60±10 minutes, mice areadministered with doses of 7.19 Gy, 7.96 Gy, 8.73 Gy, 9.50 Gy and 9.90Gy to the whole body using a 6 MV LINAC photon source (TrueBeam STxsource). Animals are irradiated at a dose rate of up to 80 cGy/min tothe midline of the animals, in which the source will irradiate animalsto 50% of the dose from anterior-posterior direction and completeirradiation from the posterior-anterior direction. Dose measurementswill be performed with a PTW 31010 0.1 cc Semiflex Ion chamber.Following administration of the TBI dose, there is a 30-day observationperiod.

All surviving animals are observed for mortality and moribundity twicedaily at least 6 hours apart for the duration of the study. In addition,all surviving animals are observed once daily for clinical signs (e.g.,unusually low or high pap activity, lethargy, shivering, appearance offur, bloody and water stool, and other symptoms of moribundity) at 1-2hours post-irradiation and once daily on non-dosing days until the endof the study. All observations are individually recorded.

TABLE 3 Dose Groups Group TBI TBI Dose Number Dose Dose VolumeConcentration Number Compound Level (Gy) of Animals (mg/kg) (mL/kg)(mg/mL) 1 Vehicle LD_(20/30) 7.19 35 0 10 0 2 Vehicle LD_(40/30) 7.96 150 10 0 3 Vehicle LD_(60/30) 8.73 15 0 10 0 4 Vehicle LD_(80/30) 9.50 150 10 0 5 Vehicle LD_(100/30) 9.90 11 0 10 0 6 PrC-210 LD_(20/30) 7.19 351,000 10 100 7 PrC-210 LD_(40/30) 7.96 15 1,000 10 100 8 PrC-210LD_(60/30) 8.73 15 1,000 10 100 9 PrC-210 LD_(80/30) 9.50 15 1,000 10100 10 PrC-210 LD_(100/30) 9.90 11 1,000 10 100 11 DzCH2SH LD_(20/30)7.19 35 1,000 10 100 12 DzCH2SH LD_(40/30) 7.96 15 1,000 10 100 13DzCH2SH LD_(60/30) 8.73 15 1,000 10 100 14 DzCH2SH LD_(80/30) 9.50 151,000 10 100 15 DzCH2SH LD_(100/30) 9.90 11 1,000 10 100

Example 29. Analogues of DzCH2SH

The compounds of this disclosure include (1,4-diazepan-6-yl)methanethiol(DzCH2SH) and derivatives or analogues thereof (Table 2).

TABLE 2 Analogues of DzCH2SH Compound Structure IUPAC Name 24

[(1R,4s,7S)-2,6- diazabicyclo[5.1.0]octan-4- yl]methanethiol 25

[(1R,4r,7S)-2,6- diazabicyclo[5.1.0]octan-4- yl]methanethiol 26

(1,5-diazocan-3-yl)methanethiol 27

{3,7-diazabicyclo[3.3.1]nonan-1- yl}methanethiol 28

(1-methyl-1,4-diazepan-6- yl)methanethiol 29

[1-(4-fluorobutyl)-1,4-diazepan-6- yl]methanethiol 30

(1-ethyl-1,4-diazepan-6- yl)methanethiol 31

[7-(methoxymethyl)-1,5-diazocan-3- yl]methanethiol 32

[(1R,4S,7S)-2,6- diazabicyclo[5.2.0]nonan-4- yl]methanethiol 33

[(1R,4S,7S)-2,6- diazabicyclo[5.2.0]nonan-4- yl]methanethiol 34

[1-(pyridin-2-yl)-1,4-diazepan-6- yl]methanethiol 35

[(3S,5aR,8aS)- decahydrocyclopenta[b][1,4] diazepin-3-yl]methanethiol 36

[(3S,5aR,8aS)- decahydrocyclopenta[b][1,4] diazepin-3-yl]methanethiol 37

[6-(sulfanylmethyl)-1,4-diazepan-6- yl]methanethiol 38

[(5aR,9aR)-decahydro-1H-1,5- benzodiazepin-3-yl]methanethiol 39

(1,4-diazepan-2-yl)methanethiol 40

(1,4-diazepan-5-yl)methanethiol 41

2-[(2S,5S)-5-methylpiperazin-2- yl]ethane-1-thiol 42

[(3S,8aS)-octahydropyrrolo[1,2- a]pyrazin-3-yl]methanethiol 43

[(2S,5S)-2-methyl-1,4-diazepan-5- yl]methanethiol 44

2-[(2S,5S)-5-(propan-2-yl)piperazin- 2-yl]ethane-1-thiol 45

[(2S,5S)-5-ethylpiperazin-2- yl]methanethiol 46

2-[(2S,5S)-4-cyclobutyl-5- methylpiperazin-2-yl]ethane-1-thiol 47

[(2R,5R)-5-methylpiperazin-2- yl]methanethiol 48

[(2S,5S)-2-tert-butyl-1,4-diazepan- 5-yl]methanethiol 49

[(2S,5S)-1,2-dimethyl-1,4-diazepan- 5-yl]methanethiol 50

[2-((2R,4aS,8aS)- decahydroquinoxalin-2yl)ethane-1- thiol]

Example 30. Synthesis of3-(methylamino)-2-((methylamino)methyl)propane-1-thiol) (PrC-210 diHCl)

PrC-210 is synthesized according to Scheme 30. Double chloridedisplacement from 3-chloro-2-(chloromethyl)prop-1-ene with twoequivalents of tert-butyl methylcarbamate followed using sodium hydrideand dimethylformamide (DMF) furnishes the corresponding di-tert-butyl(2-methylenepropane-1,3,-diyl)bis(methylcarbamate). The di-tert-butylintermediate is converted to3-(methylamino)-2-((methylamino)methyl)propane-1-thiol) (PrC-210) aftersubsequent treatment with 1) borane, 2) hydrogen peroxide, sodiumhydroxide, 3) carbon tetrabromide (CBr4)/tetraphenylporphyrin (TPP), 4)addition of a hydrosulfide group with sodium hydrosulfide and base. Theaddition of anhydrous HCl leads to formation of the PrC-210dihydrochloride salt form.

Example 31. Alternative Synthesis of ((1,4-diazepan-6-yl)methanethiolHBr) (Compound 22 diHCl, DzCH2SH)

Compound 22 is alternatively prepared according to Scheme 31. Halogenexchange of 3-chloro-2-(chloromethyl)prop-1-ene upon treatment withsodium iodide in acetone affords 3-iodo-2-iodomethylpropene. Cyclizationof N,N′-(ethane-1,2-diyl)bis(4-methylbenzenesulfonamide) with3-iodo-2-iodomethylpropene gives the corresponding olefin, followed byhydroboration-oxidation generates the corresponding sulfonamide alcohol.The alcohol is converted to di-tert-butyl6-(mercaptomethyl)-1,4-diazepane-1,4-dicarboxylate on treatment withcarbon tetrabromide (CBr4)/tetraphenylporphyrin (TPP) and sodiumhydrosulfide and base. Subsequent removal of the tert-butyl formategroups in anhydrous hydrochloride results in the dihydrochloride saltform of compound 22.

Example 32: Alternative Synthesis of (2-(piperazin-2-yl)propane-2-thiol)(Compound 21 di HCl, 2Pip-2PrSH)

Compound 21 is alternatively prepared according to Scheme 32.2-amino-3-((4-methoxybenzyl)thio)-3-methylbutanoic acid is treated with2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (Boc-ON) to add atert-butyl formate group and generate2((tert-butoxycarbonyl)amino)-3-((4-methoxybenzyl)thio)-3-methylbutanoicacid. Subsequently, glycine methyl ester (Gly-OMe) anddiisopropylethylamine (DIEA)/hexafluorophosphate azabenzotriazoletetramethyl uronium (HATU) and anhydrous hydrochloride are used togenerate methyl(2-amino-3-((4-methoxybenzyl)thio)-3-methylbutanoyl)glycinate. Themixture is refluxed in toluene for 24 hours to produce3-(2-((4-methoxybenzyl)thio)propan yl)piperazine-2,5-dione. Treatmentwith borane produces (2-((4-methoxybenzyle)thio)propan-2-yl)piperazine.After treatment with di-tert-butyl decarbonate (Boc anhydride),tert-butyl3-(2-((4-methoxybenzyl)thio)propan-2-yl)piperazine-1-carboxylate isformed and is treated with 2,2,2-Trifluoroacetic acid (TFA) and isprocessed in a Cl⁻anion exchange resin to generate Compound 21 as a diHCl salt form.

Example 33. Synthesis of [(1R, 4s, 7S)-2, 6 diazabicyclo[5.1.0]octan-4-yl]methanethiol (Compound 24) and [(1R, 4r, 7S)-2,6-diazabicyclo [5.1.0]octan-4-yl]methanethiol (Compound 25)

Compounds 24 and 25 are prepared according to Scheme 33. Halogenexchange of 3-chloro-2-(chloromethyl)prop-1-ene upon treatment withsodium iodide in acetone affords 3-iodo-2-iodomethylpropene. (1R,2S)-cyclopropane-1,2-diamine is converted to di-tert-butyl((1R,25)-cyclopropane-1,2,-diyl)dicarbamate) with the addition ofdi-tert-butyl decarbonate. Subsequent addition of3-iodo-2-iodomethylpropene leads to cyclization of di-tert-butyl((1R,25)-cyclopropane-1,2,-diyl)dicarbamate), forming di-tert-butyl(1R,7S)-4-methylene-2,6-diazabicyclo[5.1.0]octane-2,6-dicarboxylate.Subsequent hydroboration-oxidation generates isomers that are separatedby silica chromatography or fractional crystallization. Treatment ofeach isomer with carbon tetrabromide (CBr4)/tetraphenylporphyrin (TPP)and sodium hydrosulfide and base converts the hydroxide group to a thiolgroup, then subsequent treatment with anhydrous hydrochloride results inthe dihydrochloride salt form of compound 24 or compound 25.

Example 34. Synthesis of (1,5-diazocan-3-yl)methanethiol (Compound 26)

Compound 26 is prepared according to Scheme 34.(1,5-diazocan-3-yl)methanethiol (Compound 26) can be synthesized bysimilar methods as described in Example 32 using the appropriate diamine(e.g., propane-1,3,-diamine).

Example 35. Synthesis of[(1R,4R,7S)-2,6-diazabicyclo[5.2.0]nonan-4-yl]methanethiol (Compound 32)and [(1R,4S,7S)-2,6-diazabicyclo[5.2.0]nonan-4-yl]methanethiol (Compound33)

Compounds 32 and 33 are prepared according to Scheme 35.[(1R,4R,7S)-2,6-diazabicyclo[5.2.0]nonan-4-yl]methanethiol (Compound 32)and [(1R,45,75)-2,6-diazabicyclo[5.2.0]nonan-4-yl]methanethiol (Compound33) can be synthesized by similar methods as described in Example 32using the appropriate diamine (e.g., a cyclobutene-1,2,-diamineincluding (1R,25)-cyclobutane-1,2-diamine) and separating the desiredisomer.

Example 36. Synthesis of[(3R,5aR,8aS)-decahydrocyclopenta[b][1,4]diazepin-3-yl]methanethiol(Compound 35) and[(3S,5aR,8aS)-decahydrocyclopenta[b][1,4]diazepin-3-yl]methanethiol(Compound 36)

Compounds 35 and 36 are prepared according to Scheme 36.[(3R,5aR,8aS)-decahydrocyclopenta[b][1,4]diazepin-3 -yl]methanethiol(Compound 35) and [(3S,5aR,8aS)-decahydrocyclopenta[b][1,4]diazepin-3-yl]methanethiol(Compound 36) can be synthesized by similar methods as described inExample 32 using the appropriate diamine (e.g., acyclopentane-1,2,-diamine including (1R,2S)-cyclopentane-1,2-diamine)and separating the desired isomer.

Example 37. Synthesis of[(5aR,9aR)-decahydro-1H-1,5-benzodiazepin-3-yl]methanethiol (Compound38)

Compound 38 is prepared according to Scheme 37.[(5aR,9aR)-decahydro-1H-1,5-benzodiazepin-3-yl]methanethiol (Compound38) can be synthesized by similar methods as described in Example 32using the appropriate diamine (e.g., a cyclopentane-1,2,-diamineincluding (1R,25)-cyclopentane-1,2-diamine) and separating the desiredisomer.

Example 38. Synthesis of[(3R,8aS)-octahydropyrrolo[1,2-a]pyrazin-3-yl]methanethiol (Compound 42)

Compound 42 is prepared according to Scheme 38. In the presence of 48%hydrogen bromide (HBr), reflux,((3R,8aS)-oxtahyddropyrrolo[1,2-a]pyrazin-3-yl)methanol is converted to(3R,8aS)-3-(bromomethyl)octahydro-1H-pyrrolo[1,2-a]pyrazine-2,5-diium.Subsequently, addition of sodium hydrosulfide, then HBr, leads to thesynthesis of [(3R,8aS)-octahydropyrrolo[1,2-a]pyrazin-3-yl]methanethiol(Compound 42) as the diHBr salt.

Example 39. Alternative Synthesis of[(3R,8aS)-octahydropyrrolo[1,2-a]pyrazin-3-yl]methanethiol (Compound 42)

Compound 42 is prepared according to Scheme 39. In the presence of4-toluenesulfonyl chloride, and then (4-methoxyphenyl)methanethiol,((3R,8aS)-oxtahyddropyrrolo[1,2-a]pyrazin-3-yl)methanol is converted to(3R,8aS)-3-(((4-methoxybenzyl)thio)methyl)-2-tosyloctahydropyrrolo[1,2-a]pyrazine.Subsequent addition of 48% hydrobromide (HBr), phenol, reflux leads tothe synthesis of[(3R,8aS)-octahydropyrrolo[1,2-a]pyrazin-3-yl]methanethiol (Compound 42)as the diHBr salt.

Example 40. Synthesis of[(2S,5S)-2-methyl-1,4-diazepan-5-yl]methanethiol (Compound 43)

Compound 43 is prepared according to Scheme 40. Treatment of[(S)-3-(((benzyloxy)carbonyl)amino)-4-(tert-butoxy)-4-oxobutanoic acid]with isobutyl chloroformate (i-BuOCOCl) and triethylamine (Et₃N) intetrahydrofuran (THF), followed by sodium borohydride (NaBH₄) in waterforms tert-butyl ((benzyloxy)carbonyl)-L-homoserinate. Chromatography(PCC/silica gel) in dichloromethane (CH₂Cl₂), then reaction with benzyl(S)-alaninate, sodium cyanoborohydride (NaCNBH₃) in acetic acid-methanolforms the tert-butyl(S)-4-(((S)-1-(benzyloxy)-1-oxopropan-2-yl)amino)-2-(((benzyloxy)carbonyl)amino)butanoate.Subsequent treatment with HCO₂ ⁻ NH₄ ⁺ in 10% Pd/C in methanol-aceticacid*H₂O and HATU, DIPEA in DMF leads to formation of tert-butyl(2S,5S)-2-methyl-3-oxo-1,4-diazepane-5-carboxylate. Subsequent treatmentwith lithium aluminum hydride (LAH), Boc-ON and 4-toluenesulfonylchloride forms di-tert-butyl(2S,5S)-2-methyl-5-((tosyloxy)methyl)-1,4-diazepane-1,4-dicarboxylate.Subsequent treatment with sodium hydrosulfide plus a base, thentrifluoroacetic acid (TFA) forms[(2S,5S)-2-methyl-1,4-diazepan-5-yl]methanethiol (Compound 43).

Example 41. Alternative Synthesis of [(2S,5S)-2-methyl-1,4-diazepan-5-yl]methanethiol (Compound 43)

Compound 43 is prepared according to Scheme 41. In the presence of HATUand benzyl (S)-alaninate,[(S)-3-(((benzyloxy)carbonyl)amino)-4-(tert-butoxy)-4-oxobutanoic acid]is converted to tert-butyl(S)-4-(((S)-1-(benzyloxy)-1-oxopropan-2-yl)amino)-2-(((benzyloxy)carbonyl)amino)butanoate.Subsequent treatment with HCO₂ ⁻ NH₄ ⁺ in 10% Pd/C in methanol-aceticacid*H₂O and HATU, DIPEA in DMF leads to formation of tert-butyl(2S,5S)-2-methyl-3,7-dioxo-1,4-diazepane-5-carboxylate. Subsequenttreatment with lithium aluminum hydride (LAH), Boc-ON and4-toluenesulfonyl chloride forms di-tert-butyl(2S,5S)-2-methyl-5-((tosyloxy)methyl)-1,4-diazepane-1,4-dicarboxylate.Subsequent treatment with sodium hydrosulfide plus a base, thentrifluoroacetic acid (TFA) forms[(25,5S)-2-methyl-1,4-diazepan-5-yl]methanethiol (Compound 43) as thediTFA salt.

Example 42. Synthesis of[2-((2R,4aS,8sS)-decahydroquinoxalin-2-yl)ethane-1-thiol](Compound 50)

Compound 50 is prepared according to Scheme 42.(1S,2S)-cyclohexane-1,2-diamine is combined with diethyl but-2-ynedioatein the presence of ethanol and heat to form ethyl2-((2R,4aS,8aS)-3-oxodecahydroquinoxalin-2-yl)acetate. Subsequentaddition of lithium aluminum hydride (LAH) or borane (BH3) forms2-((2R,4aS,8aS)-decahydroquinoxalin-2-yl)ethan-1-ol, then subsequentaddition of di-tert-butyl decarbonate ((Boc)₂O forms di-tert-butyl(2R,4aS,8aS)-2-(2-((tert-butoxycarbonyl)oxy)ethyl)octahydroquinoxaline-1,4-dicarboxylate.Subsequent addition of potassium carbonate forms di-tert-butyl(2R,4aS,8aS)-2-(2-hydroxyethyl)octahydroquinoxaline-1,4-dicarboxylate.When reacted with (4-methoxyphenyl)methanethiol, di-tert-butyl(2R,4aS,8aS)-2-(2-((4-methoxybenzyl)thio)ethyl)octahydroquinoxaline-1,4-dicarboxylateis formed. Subsequent treatment with trifluoroacetic acid (TFA).O-cresol, reflux forms[2-((2R,4aS,8aS)-decahydroquinoxalin-2-yl)ethane-1-thiol] (Compound 50)as the diTFA salt.

Example 43. Synthesis of3-(methylamino)-2-((methylamino)methyl)propane-1-thiol) (PrC-210 diHCl)

PrC-210 was synthesized according to Scheme 43. In Reaction A:Tert-Butylmethylcarbamate (CAS: 16066-84-5), 10 grams, 0.076 moles and50 ml dry dimethylformamide (DMF) were added to a flame-dried roundbottom flask, under argon, that was set up for magnetic stirring. Theflask was cooled in an ice bath, then sodium hydride, 3.34 grams, 1.1eq. (60% dispersion in mineral oil, Aldrich #452912) was added portionwise over 10 minutes (caution, gas evolution) and the reaction wasallowed to stir for 1 hour while warming to room temperature.3-chloro-2-chloromethyl-1-propene (CAS: 1871-57-4, Aldrich #C31104),3.80 g, 0.4 eq. pre-dried over 4A molecular sieves, in 3 ml anhydrousDMF, was added to this mixture slowly over 15 min at room temperature.The reaction was then heated to 60° C. for 24 hours until the reactionwas determined to be complete using TLC. The reaction was then cooled inan ice bath and quenched with aqueous saturated NaCl and extracted withethyl acetate, (3×100 ml). The combined extracts were dried over MgSO4,filtered, concentrated. The crude material was purified by silica gelflash column chromatography eluting with hexane/ethylacetate mixturesproviding 6.8 grams (71%) of compound II (i.e., di-tert-butyl(2-methylenepropane-1,3-diyl)bis(methylcarbamate)) as a solid. Thestructure was confirmed by NMR.

In Reaction B: Compound II, 6 grams, 0.018 moles and 35 ml anhydrous THFwere added to a flame-dried round bottom flask, under argon, set up formagnetic stirring. The reaction was cooled to 0° C. A solution of boranein THF, 1M (Aldrich #176192), 19.8 mL, 1.1 eq. was added via syringe andthe reaction was allowed to warm up to room temperature and allowed tostir for 1 hour. TLC analysis (10% EtOAc in Hexane) showed completedisappearance of starting material. The reaction was opened to the airand quenched with 1 ml H₂O, added dropwise. NaOH, 3M solution (25 ml)was then added followed by dropwise addition of 5 ml of 30% H₂O₂ keepingthe solution close to room temperature with an ice bath as needed. Thereaction was stirred for another hour at room temperature. Solid NaClwas added until the solution was saturated and the mixture was extractedwith ethyl acetate, (3×100 ml). The combined extracts were dried overMgSO₄, filtered and concentrated. The crude material was purified bysilica gel flash column chromatography eluting with hexane/ethylacetatemixtures providing 5.2 grams (84%) of compound III (i.e., di-tert-butyl(2-(hydroxymethyl)propane-1,3-diyl)bis(methylcarbamate)) as a solid.Structure was confirmed by NMR, MS. Purity by TLC.

In Reaction C: A solution of 5 grams, 0.015 moles, of compound III(dried in vacuo over P₂O₅) in 50 mL of dry dichloromethane andmagnetically stirred under argon at room temperature was treated with6.5 grams, 1.3 eq CBr₄. The solution was then cooled (−30° C.) andtriphenylphosphine 5.3 grams, 1.35 eq. was added in 3 portions over 30minutes. The reaction was allowed to reach 0° C. over 30 minutes andmaintained at that temperature for 4 hours. TLC analysis (10% EtOAc inHexane) of the reaction showed complete conversion of the startingmaterial. The mixture was concentrated and applied to a silica gelcolumn and eluted with mixtures of dichloromethane and methanol ofincreasing polarity. The combined fractions were pooled and evaporatedproviding compound IV as a low-melting waxy solid, 5.35 grams (90%). Thestructure was confirmed by NMR, MS. The purity was determined by TLC.

In Reaction D: 25 ml of distilled anhydrous THF was added to compoundIV, 5 g, 0.013 moles, in a flask under argon and equipped for magneticstirring and cooled to −10° C. Hexamethyldisilathiane, CAS 3385-94-2(Aldrich #283134), 2.78 grams, 1.2 eq. was added followed by dropwiseaddition of Tetrabutylammonium fluoride solution, 1 M in THF, (TBAF,Aldrich #216143) 15.6 mL, 1.2 eq over 5 minutes. The reaction wasstirred at −10° C. for 30 minutes and then allowed to warm to roomtemperature over 30 minutes. TLC analysis (5% EtOAc in Hexane) showeddisappearance of starting material. The reaction was quenched with 10 mLof saturated NH₄Cl solution. The mixture was extracted with ethylacetate, (3×100 mL). The combined extracts were washed with brine, driedover MgSO₄, filtered and concentrated. The crude material was purifiedby silica gel flash column chromatography and eluted withhexane/ethylacetate mixtures providing 3.7 grams (82%) of compound V asa waxy solid. The structure was confirmed by NMR, MS and the puritydetermined by TLC. The compound had a characteristic thiol-like odor.

In Reaction E: 48 ml of HCl in methanol, 6 eq. (1.25 M solution, Aldrich#17935) was added to a solution of compound V, 3.5 g, 0.010 molesdissolved in 10 ml dry methanol in a flask under argon and equipped formagnetic stirring and the reaction was stirred at room temperature for24 hours. TLC analysis (20% EtOAc in Hexane) showed the disappearance ofstarting material and the appearance of a highly polar compound thatstained positive with ninhydrin. The solution was degassed by gentlybubbling argon into the solution for 30 minutes. Concentration (rotaryevaporator at ambient temperature) provided a crude oily residue whichwas triturated with hexane producing a white solid. The hexane wasremoved (via pipette suction) and replaced with dry THF (25 ml). Afteran additional 10 minutes of trituration, the THF was removed andreplaced with dry hexane (25 ml). After an additional 10 minutes oftrituration, the hexane was removed and the resulting white solid wasdried in vacuo over P₂O₅ providing 1.95 grams of diHCl salt of PrC-210(88%). A 10 minutes exposure of a small amount of PrC-210 to theatmosphere did not show any signs of hygroscopicity. PrC-210 showed HPLCpurity of >98%, NMR and MS were fully consistent with the structure.

Example 45. Synthesis of ((1,4-diazepan-6-yl)methanethiol HBr) (Compound22 HCl, DzCH2SH)

Compound 22 was synthesized according to Scheme 45. In Reaction F:Di-tert-butyl ethane-1,2-diyldicarbamate (compound VI; CAS: 33105-93-0,Combi-Blocks #QK-1806), 10 grams, 0.038 moles and 150 ml drydimethylformamide (DMF) were added to a flame-dried round bottom flask,under argon, set up for magnetic stirring. The flask was cooled in anice bath, then sodium hydride, 3.38 grams, 2.2 eq. (60% dispersion inmineral oil, Aldrich #452912) was added portion wise over 10 minutes(caution, hydrogen gas evolution) and the reaction was allowed to stirfor 1 hour while warming to room temperature.3-chloro-2-chloromethyl-1-propene (CAS: 1871-57-4, Aldrich #C31104), 4.8grams, 1.0 eq., pre-dried over 4A molecular sieves, in 6 ml anhydrousDMF was rapidly added to the mixture at room temperature. The reactionwas then heated to 60° C. for 24 hours and the reaction was determinedto be complete by TLC. The reaction was then cooled in an ice bath andquenched with aqueous saturated NaCl and extracted with ethyl acetate,(3×100 ml). The combined extracts were dried over MgSO₄, filtered andconcentrated. The crude material was purified by silica gel flash columnchromatography eluting with hexane/ethylacetate mixtures providing 7.4grams (63%) of compound VII as a solid. The structure was confirmed byNMR and MS.

In Reaction G: compound VII, 7 grams, 0.022 moles and 42 mL anhydrousTHF were added to a flame-dried round bottom flask, under argon,equipped for magnetic stirring. The reaction was cooled to 0° C. Asolution of borane in THF, 1M (Aldrich #176192), 24.2 mL, 1.1 eq. wasadded via syringe and the reaction was allowed to warm up to roomtemperature and allowed to stir for 1 hour. TLC analysis showed completedisappearance of starting material. The reaction was opened to the airand quenched with 2 mL H₂O added dropwise. NaOH, 3M solution (30 mL) wasthen added followed by dropwise addition of 6 mL of 30% H₂O₂ keeping thesolution close to room temperature with an ice bath as needed. Thereaction was stirred for another hour at room temperature. Solid NaClwas added until the solution was saturated and the mixture was extractedwith ethyl acetate, (3×100 ml). The combined extracts were dried overMgSO₄, filtered and concentrated. The crude material was purified bysilica gel flash column chromatography eluting with hexane/ethylacetatemixtures providing 6.14 grams (83%) of compound VIII as a solid. Thestructure was confirmed by NMR.

In Reaction H: A solution of 6 grams, 0.018 moles, of compound VIII(dried in vacuo over P₂O₅) in 75 mL of dry dichloromethane andmagnetically stirred under argon at room temperature was treated with7.8 grams, 1.3 eq CBr₄. The solution was then cooled (−30° C.) andtriphenylphosphine 6.37 grams, 1.35 eq. was added in 3 portions over 30minutes. The reaction was allowed to reach 0° C. over 30 minutes andmaintained at that temperature for 4 hours. TLC of the reaction showedcomplete conversion of starting material. The mixture was concentratedand applied to a silica gel column and eluted with mixtures ofdichloromethane and methanol of increasing polarity. The combinedfractions were pooled and evaporated providing compound IX as a viscousoil, 6.21 grams (87%). The structure was confirmed by NMR.

In Reaction I: 25 ml of distilled anhydrous THF was added to compoundIX, 4 grams, 0.010 moles, in a flask under argon and equipped formagnetic stirring and was cooled to −10° C. Hexamethyldisilathiane, CAS3385-94-2 (Aldrich Cat #283134), 2.18 grams, 1.2 eq. was added, followedby dropwise addition of tetrabutylammonium fluoride solution, 1 M inTHF, (TBAF, Aldrich Cat #216143) 12.0 mL, 1.2 eq. over 5 minutes. Thereaction was stirred at -10° C. for 30 minutes and then allowed to warmto room temperature over 30 minutes. TLC analysis showed disappearanceof starting material. The reaction was quenched with 10 mL of saturatedNH₄Cl solution. The mixture was extracted with ethyl acetate, (3×100ml). The combined extract was washed with brine, dried over MgSO₄,filtered and concentrated. The crude material was purified by silica gelflash column chromatography eluting with hexane/ethylacetate mixturesproviding 2.88 grams (83%) of compound X as a waxy solid. The structurewas confirmed by NMR and the compound had a characteristicmercaptan-like order.

In Reaction J: 34 ml of HCl in methanol, 6 eq. (1.25 M solution, AldrichCat #17935) was added to a solution of compound X, 2.5 grams, 0.007moles dissolved in 10 mL dry methanol in a flask under argon andequipped for magnetic stirring and the reaction was stirred at roomtemperature for 24 hours. TLC analysis showed the disappearance ofstarting material and the appearance of a highly polar compound thatstained positive with ninhydrin. The solution was degassed by gentlybubbling argon into the solution for 30 minutes. The concentration(rotary evaporator at ambient temp) provided a crude oily residue whichwas triturated under argon with hexane producing a white solid. Thehexane was removed (via pipette suction) and replaced with dry THF (20mL). After a further 10 minutes of trituration under argon, the THF wasremoved and replaced with dry hexane (20 mL). After an additional 10minutes of trituration under argon, the hexane was removed and theresulting white solid was dried in vacuo over P₂O₅ providing 1.4 g ofCompound 22 (91%). A 10 minute exposure of a small amount of DzCH2SH tothe atmosphere did not show any signs of hygroscopicity. The DzCH2SH asthe diHCl salt produced in this manner showed HPLC purity of >98%, andNMR and MS analysis were fully consistent with the structure.

Example 46: Synthesis of (2-(piperazin-2-yl)propane-2-thiol) (Compound21, 2Pip-2PrSH)

Compound 21 was synthesized according to Scheme 46. In Reaction K:2-Amino-3-((4-methoxybenzyl)thio)-3-methylbutanoic acid (compound XI),10 grams, 0.037 moles was placed in a round-bottom flask, equipped formagnetic stirring and 200 mL 1:1 mixture of THF/H20 was added. The flaskwas cooled in an ice bath and BOC anhydride, 9.71 grams, 1.2 eq.(Aldrich #34660) was added in one portion followed by sodium bicarbonate(NaHCO₃) 3 grams, 5 eq. and the reaction was allowed to stir for 1 hour.Subsequently, the flask was removed from the ice bath and stirred for 14hours at room temperature. The reaction was determined to be complete byTLC and the THF was then stripped off using a rotary evaporator and theresulting mixture was treated with NaCl (saturation) and extracted withethyl acetate, (3×200 ml). The combined extracts were dried over MgSO₄,then filtered and concentrated. The resulting solid was purified byrecrystallization with ethanol providing 13.1 grams (94%) of compoundXII as a white solid. The structure was confirmed by NMR and MS.

In Reaction L: Compound XII, 12 grams, 0.032 moles was placed in aflame-dried round bottom flask, under argon, equipped for magneticstirring along with glycine methylester, 2.85 grams, 1 eq. followed by100 mL anhydrous dimethylformide. To this solution was addeddiisopropylethylamine (DIEA, Aldrich 387649) 4.95 grams, 1.2 eq.followed byN-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide, (HATU, Aldrich 445460) 13.4 grams, 1.1 eq.and the reaction was stirred overnight at room temperature. TLC analysisindicated that the reaction was complete. The reaction was poured into400 mL of ice-cold water and stirred while warming to room temperature.The resulting precipitate was collected by filtration and washed withdistilled water (100 mL) followed by diethyl ether (25 mL) and dried invacuo over P₂O₅ providing 13.5 grams of intermediate BOC-protectedamide, without further purification. The BOC group was removed by firstdissolving the intermediate (11.5 g) in 75 mL dry methanol in a flaskunder argon, equipped for magnetic stirring. Then a solution of HCl inmethanol, 52 mL, 2 eq. (1.25 M solution, Aldrich Cat #17935) was addedand the reaction was stirred at room temperature for 24 hours. TLCanalysis showed the disappearance of starting material and theappearance of a more polar product that stained positive with ninhydrin.The solution was degassed by bubbling argon into the solution for 30minutes. The solution was made alkaline by addition of excess 1 Maqueous NaOH (with cooling) and the resulting solution was extractedwith dichloromethane (3×200 mL) followed by concentration (rotaryevaporator) which provided a crude oily residue. Flash columnchromatography with CH₂Cl₂/CH₃OH mixtures provided pure compound XIII, 78 grams, 72% yield as a waxy solid. The structure was confirmed by NMRand MS.

In Reaction M: Compound XIII, 7 grams, 0.020 moles, was placed in around-bottom flask equipped for magnetic stirring, then 100 mL toluenewas added and the flask was fitted with a condenser. The solution wasrefluxed for 24 hours whereupon TLC analysis showed a complete reaction.The solution was concentrated and the crude product was then subjectedto flash column chromatography on silica gel eluting with CH₂Cl₂/CH₃OHmixtures which provided pure compound XIV, 4.3 grams, 68% yield as awhite solid. The structure was confirmed by NMR and MS.

In Reaction N: Compound XIV, 4 grams, 0.013 moles and 10 mL anhydrousTHF were added to a flame-dried round bottom flask, under argon,equipped for magnetic stirring. A solution of borane in THF, 1M (Aldrich#176192), 39 mL, 3 eq. was added slowly via syringe. The reaction wasthen refluxed for 4 days. TLC analysis shows complete disappearance ofstarting material. The reaction was opened to the air and quenched with5 mL H₂O. The reaction was stirred for another 30 minutes at roomtemperature. The solution was then concentrated to dryness using arotary evaporator and the solids washed exhaustively withchloroform/methanol (1:1) solution, 200 mL. The combined washings wereconcentrated and the crude product (3.6 grams of compound XV) wascarried directly into the subsequent reaction without purification.

In Reaction O: the crude product compound XV was BOC-protected so itcould be purified by column chromatography. Crude compound XV, 3.6grams, 0.013 moles was placed in a round-bottom flask equipped formagnetic stirring and 50 mL 1:1 mixture of THF/H₂O was added. The flaskwas cooled in an ice bath and BOC anhydride, 3.1 grams, 1.2 eq. (Aldrich#34660) was added in one portion followed by sodium bicarbonate (NaHCO₃)5.4 grams, 5 eq. and the reaction was allowed to stir for 1 hour, thenremoved from the ice bath and was stirred for 14 hours at roomtemperature. The reaction was determined to be complete by TLC. The THFwas then stripped off using a rotary evaporator and the resultingmixture was treated with NaCl (saturation) and extracted with ethylacetate, (4×50 mL). The combined extracts were dried over MgSO₄,filtered and concentrated. The resulting solid was purified by flashcolumn chromatography on silica gel eluting with CH₂Cl₂/CH₃OH mixtureswhich provided pure compound XVI, x 2.4 grams, 49% yield from compoundXIV as a white solid. The structure was confirmed by NMR and MS.

In Reaction P: Compound XVI, 2.2 grams, 0.0058 moles was placed in around-bottom flask equipped for magnetic stirring followed by 15 mLanhydrous trifluoroacetic acid (CF₃COOH, Aldrich #8.08260). The flaskwas fitted with a condenser and the solution was refluxed for 5 hourswhereupon it was determined that the reaction was complete using TLC byobserving the disappearance of starting material and the appearance of ahighly polar product, which stained positive with ninhydrin. Thesolution was concentrated using a rotary evaporator to a solid residue.This crude product was converted to the free base by first adding 20 mLof CH₂Cl₂/CH₃OH (1:1) to the flask under an argon atmosphere with amagnetic stir bar. Then Amberlyst A-21 ion exchange resin, 6 grams (AlfaAesar # A17956), which was prewashed by three successive treatments with20 mL of CH₂Cl₂/CH3OH (1:1), was added to the solution. The mixture wasstirred at room temperature for 3 hours followed by rapid filtrationunder argon. The resin was washed with an additional 20 mL CH₂Cl2/CH₃OH(1:1) and was concentrated using a rotary evaporator at roomtemperature, forming a waxy residue. This waxy residue product was thenconverted to the HCl salt by adding the residue to 10 mL dry methanolfollowed by addition of 14.5 mL of HCl in methanol, 2.5 eq. (1.25 Msolution, Aldrich Cat #17935), which produced a clear solution which wasallowed to stand for 15 minutes. The solution was then degassed bybubbling argon through the solution for 15 minutes. Concentrating with arotary evaporator at ambient temperature provided a crude residue whichwas triturated under argon with hexane (25 mL) produced a white solid.The hexane was removed (via pipette suction) and replaced with dry THF(10 mL). After an additional 10 minutes of trituration under argon, theTHF was removed and replaced with dry hexane (20 mL). After anadditional 10 minutes of trituration under argon, the hexane was removedand the resulting white solid was dried in vacuo over P₂O₅ providing 1.2grams of Compound 21 as the diHCl salt (89%). A 10-minute exposure of asmall amount of Compound 22 to the atmosphere did not show any signs ofhygroscopicity. The compound produced in this manner showed HPLC purityof >98%, and NMR and MS analysis were consistent with the structure.

Example 47. Synthesis of [(3R,8aS)-octahydropyrrolo[1,2-a]pyrazin-3-yl]methanethiol (Compound 42)

Compound 42 is prepared according to Scheme 47. BOC anhydride is addedto ((3R, 8aS)-octahydropyrrolo[1,2-a]pyrazin-3-yl)methanol and chilled(e.g., −20° C.) to form tert-butyl(3R,8aS)-3-(hydroxymethyl)hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate.Subsequently, MsCl and triethanolamine (TEA) is added to form tert-butyl(3R,8aS)-3-(((methylsulfonyl)oxy)methyl)hexahydropyrrolo[1,2-a]pyrzine-2(1H)-carboxylate.Next, Bis(trimethylsilyl)sulfide ((TMS)₂S) and tetra-n-butylammoniumfluoride (TBAF) is added to to form tert-butyl(3R,8aS)-3-(mercaptomethyl)hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate.Then excess of HCl leads to the synthesis of[(3R,8aS)-octahydropyrrolo[1,2-a]pyrazin-3-yl]methanethiol (Compound 42)as the diHCl salt.

Example 48. Synthesis of[2-((2R,4aS,8aS)-decahydroquinoxalin-2-yl)ethane-1-thiol] (Compound 50)

Compound 50 is prepared according to Scheme 48.(1S,25)-cyclohexane-1,2-diamine and dimethyl but-2-ynedioate arecombined and heated in the presence of ethanol to form methyl 2-((4aS,8aS,Z)-3-oxooctahydroquinoxalin-2(1H)-ylidene)acetate. Subsequentaddition of hydrogen and palladium (Pd) leads to the formation of twostereoisomers: 1. methyl2-((2R,4aS,8aS)-3-oxodecahydroquinoxalin-2-yl)acetate and 2. methyl2-((2S,4aS,8aS)-3-oxodecahydroquinoxalin-2-yl)acetate. When thestereoisomers are in the presence of lithium aluminum hydride or borane,2-((2R,4aS,8aS)-decahydroquinoxalin2-yl)ethan-1-ol or its isomer forms.Subsequent addition of di-tert-butyl decarbonate ((2BOC)₂O), chilled(e.g., −20° C.) forms di-tert-butyl(2R,4aS,8aS)-2-(2-hydroxyethyl)octahydroquinoxaline-1,4-dicarboxylate,or its isomer. Exposure of the intermediate to methanesulfonyl chloride(MsCl) and triethylamine forms di-tert-butyl(2R,4aS,8aS)-2-(2-((methylsulfonyl)oxy)ethyl)octahydroquinoxaline-1,4-dicarboxylate,or its isomer. Subsequent addition of bis(trimethylsilyl) sulfide((TMS)₂S) and tetra-n-butylammonium fluoride (TBAF) forms di-tert-butyl(2R,4aS,8aS)-2-(2-mercaptoethyl)octahydroquinoxaline-1,4-dicarboxylate,or its isomer. In the presence of excess HCl,2-((2R,4aS,8aS)-decahydroquinoxalin-2-yl)ethane-1-thiol (Compound 50) asthe diHCl salt, or its isomer, is formed. The stereoisomers can beoptionally separated by silica chromatography or recrystallization toyield one or both stereoisomers of the final product.

Example 49. Synthesis of[2-((2R,4aS,8aS)-decahydroquinoxalin-2-yl)ethane-1-thiol] (Compound 50)

Compound 50 is prepared according to Scheme 49.(1S,2S)-cyclohexane-1,2-diamine and dimethyl maleate are combined andheated in the presence of ethanol to form two stereoisomers: 1. methyl2-((2R,4aS,8aS)-3-oxodecahydroquinoxalin-2-yl)acetate and 2. methyl2-((2S,4aS,8aS)-3-oxodecahydroquinoxalin-2-yl)acetate. When thestereoisomers are in the presence of lithium aluminum hydride or borane,2-((2R,4aS,8aS)-decahydroquinoxalin2-yl)ethan-1-ol, or its isomer,forms. Subsequent addition of di-tert-butyl decarbonate ((2BOC)₂O),chilled (e.g., −20° C.), forms di-tert-butyl(2R,4aS,8aS)-2-(2-hydroxyethyl)octahydroquinoxaline-1,4-dicarboxylate,or its isomer. Exposure of the intermediate to methanesulfonyl chloride(MsC1) and triethylamine forms di-tert-butyl(2R,4aS,8aS)-2-(2-((methylsulfonyl)oxy)ethyl)octahydroquinoxaline-1,4-dicarboxylate,or its isomer. Subsequent addition of bis(trimethylsilyl) sulfide((TMS)₂S) and tetra-n-butylammonium fluoride (TBAF) forms di-tert-butyl(2R,4aS,8aS)-2-(2-mercaptoethyl)octahydroquinoxaline-1,4-dicarboxylate,or its isomer. In the presence of excess HCl,2-((2R,4aS,8aS)-decahydroquinoxalin-2-yl)ethane-1-thiol (Compound 50) asthe diHCl salt, or its isomer, is formed. The stereoisomers can beoptionally separated by silica chromatography or recrystallization toyield one or both stereoisomers of the final product.

What is claimed is:
 1. A compound having a structure according toformula I:

or a pharmaceutically acceptable salt, solvate, hydrate, or polymorphthereof, or a solvate, hydrate, or polymorph of the pharmaceuticallyacceptable salt, wherein; each R⁰ is independently hydrogen,(C1-C3)alkyl, or —SH; A is selected from hydrogen, Moiety A¹, Moiety A²or Moiety A³:

wherein each of R¹ and R² is independently selected from the groupconsisting of hydrogen, —(CH(R⁶))—O—C(O)R¹⁰, —(CH(R⁶))_(m)—S—C(O)R¹⁰ and—CH₂—(C(R¹¹)₂)—C(O)—CH₂—S—C(O)R¹⁰; wherein m is an integer selected fromthe group consisting of 0, 1, 2, 3, and 4; or R¹ and R², one of which isCH₂ or the other of which is CH₂CH₂, taken with the —O—P—O-linkage towhich they are attached form a 6-membered heterocycloalkyl ring that isindependently substituted with 1-2 R^(a) and 0-3 R^(b); wherein eachR^(a) is independently hydrogen, (C1-C6)alkyl, (C6-C10)aryl- or a 5- to10-membered heteroaryl-, wherein said alkyl, aryl and heteroaryl issubstituted with 0-3 R^(c), provided that at least one R^(a) group is(C6-C10)aryl- or a 5- to 10-membered heteroaryl-; wherein when present,each R^(b) is —(C1-C3)alkyl; wherein when present each R^(c) isindependently selected from the group consisting of halogen,(C1-C3)alkyl, —CN, —O—(C1-C3)alkyl, —S—(C1-C3)alkyl,—C(O)O—(C1-C3)alkyl, —N(R′)₂, —CF₃ and —OCF₃; wherein each R⁶ isindependently hydrogen or (C1-C3)alkyl;wherein each R¹⁰ is selected fromthe group consisting of —(C1-C6)alkyl, —O—(C1-C6)alkyl, —O—(C6-C10)aryl,—(C6-C10)aryl, (5- to 10-membered)heteroaryl, (4- to10-membered)heterocycloalkyl, (C3-C10)cycloalkyl, —O-(5- to10-membered)heteroaryl, —O-(4- to 10-membered)heterocycloalkyl,—O—(C3-C10)cycloalkyl, —O-(4- to 20-membered)heteroalkyl, -(4- to20-membered)heteroalkyl, —[(CH₂)_(y)O]_(z)—R, —CH₂—O—[(CH₂)_(y)O]_(z)—Rand —O—[(CH₂)_(y)O]_(z)—R, wherein each of said heteroalkyl,heterocycloalkyl and heteroaryl independently have 1-6 oxygen atoms,wherein y is an integer between 1 and 4, wherein z is an integer between1 and 10, wherein R is hydrogen or (C1-C6)alkyl, and wherein each R¹⁰ isindependently substituted with 0-3 R^(c); each R¹¹ is independentlyselected from the group consisting of hydrogen, —(C1-C6)alkyl,—CH₂—O—C(O)R″, —C(O)—OR″, -(4- to 20-membered)heteroalkyl, —O-(4- to20-membered)heteroalkyl, —[(CH₂)_(y)O]_(z)—R, —CH₂—O—[(CH₂)_(y)O]_(z)—Rand —O—[(CH₂)_(y)O]_(z)—R, wherein each of said heteroalkylindependently has 1-6 oxygen atoms, wherein y is an integer between 1and 4, wherein z is an integer between 1 and 10, and wherein R ishydrogen or (C1-C6)alkyl;

wherein W and Y are independently selected from N or CH; wherein R³ ishydrogen, halogen, (C1-C6)alkyl, (C3-C7)cycloalkyl, (5- to8-membered)heterocycloalkyl, —O—(C1-C6)alkyl, —O—(C3-C7)cycloalkyl,—O-(5- to 8-membered)heterocycloalkyl, (C2-C6)alkenyl, —CH₂OH, phenyl,(5- to 6-membered)heteroaryl, or (5- to 6-membered)heterocycloalkyl,wherein R³ is substituted with 0-3 substituents selected from the groupconsisting of halogen, oxo, cyano, —(C1-C6)alkyl, —O—(C1-C6)alkyl, and—C(O)O(C1-C3)alkyl; wherein R⁴ is hydrogen, —CN, (C1-C6)alkyl,—O—(C1-C6)alkyl, —(C2-C6)alkenyl or —CH₂OH; or R⁴ and R³ are takentogether with the carbon atoms to which they are attached to form a(C5-C6)cycloalkyl, (C6-C10)aryl, (5- to 10-membered)heterocycloalkyl or(5- to 10-membered)heteroaryl; wherein R⁵ is hydrogen, halogen,(C1-C6)alkyl or —O—(C1-C6)alkyl; or R⁵ and R⁴ are taken together withthe carbon atoms to which they are attached to form a (C5-C6)cycloalkyl,phenyl, (5- or 6-membered)heterocycloalkyl, or (5- or6-membered)heteroaryl; wherein R¹⁴ is —(C1-C6)alkyl; wherein R¹⁵ ishydrogen, —(C1-C6)alkyl, —CH2-phenyl, or —CH₂-(5-to10-membered)heteroaryl, wherein the —(C1-C6)alkyl, —CH₂-phenyl, or—CH₂-(5-to 10-membered)heteroaryl are substituted with 0-3 substituentsselected from the group consisting of —OH, —SH, —SCH₃, —C(O)NH₂,—C(O)OH, —NH₂ and —NH—C(═NH)NH₂; R¹⁶ is hydrogen or —(C1-C6)alkyl;

wherein R⁷ is selected from the group consisting of —(C1-C3)alkyl,—(C3-C6)cycloalkyl, and -(4- to 6-membered)heterocycloalkyl, wherein R⁷is substituted with 0-3 R″; wherein R⁸ and R⁹ are independently selectedfrom the group consisting of hydrogen, —(C1-C3)alkyl,—(C3-C6)cycloalkyl, and -(4- to 6-membered)heterocycloalkyl, wherein R⁸and R⁹ are independently substituted with 0-3 R″; wherein R″ ishydrogen, halogen, —(C1-C6)alkyl, —O—(C2-C6)alkyl, or -(4- to20-membered)heteroalkyl, wherein said heteroalkyl has 1-6 oxygen atoms;wherein B is a (6- to 8-membered)heterocycloalkyl containing two Natoms, Moiety B¹, or Moiety B², wherein B is substituted with a(C1-C4)alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, so as toform a bicyclic ring, and/or substituted with 0-3 (C1-C4)alkyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heteroaryl,(C1-C6)aryl, (C5 to C6)heteroaryl, (C1-C4)acyl, (C1-C4)alkenyl and(C1-C4)alkynyl, wherein the (C1-C4)alkyl, (C1-C4)alkenyl and(C1-C4)alkynyl are optionally substituted with 1-3 halogen or(C1-C4)alkoxy; wherein Moiety B¹ has the structure:

wherein each occurrence of R¹² and R¹³ is independently selected fromthe group consisting of hydrogen, —(C1-C10)alkyl, —(C3-C10)cycloalkyl,-(4- to 10-membered)heteroaryl, and -(4- to10-membered)heterocycloalkyl, wherein each of R¹² and R¹³ isindependently substituted with 0-3 R′; or wherein two R¹³ groups takenwith the nitrogen atoms to which they are attached combine to form a (7-to 8-membered)heterocycloalkyl, wherein the (7- to8-membered)heterocycloalkyl is substituted with a (C1-C4)alkyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, so as to form abicyclic ring, and/or substituted with 0-3 (C1-C4)alkyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, heteroaryl, (C1-C6)aryl, (C5 toC6)heteroaryl, (C1-C4)acyl, (C1-C4)alkenyl and (C1-C4)alkynyl, whereinthe (C1-C4)alkyl, (C1-C4)alkenyl and (C1-C4)alkynyl are optionallysubstituted with 1-3 halogen or (C1-C4)alkoxy; wherein R′ is selectedfrom hydrogen, halogen, (C1-C4)alkyl, or —O—(C1-C4)alkyl; and whereinMoiety B² has the structure:

wherein n is an integer selected from the group consisting of 1, 2, 3,and 4; and provided that the compound is not


2. The compound according to claim 1, or a pharmaceutically acceptablesalt, solvate, hydrate, or polymorph thereof, or a solvate, hydrate, orpolymorph of the pharmaceutically acceptable salt, wherein B is aheterocycle selected from the group consisting of

wherein B is optionally substituted with a (C1-C4)alkyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, so as to form a bicyclic ring,and/or substituted with 0-3 (C1-C4)alkyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, heteroaryl, (C1-C6)aryl, (C5 to C6)heteroaryl,(C1-C4)acyl, (C1-C4)alkenyl and (C1-C4)alkynyl, wherein the(C1-C4)alkyl, (C1-C4)alkenyl and (C1-C4)alkynyl are optionallysubstituted with 1-3 halogen or (C1-C4)alkoxy.
 3. The compound accordingto claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, orpolymorph thereof, or a solvate, hydrate, or polymorph of thepharmaceutically acceptable salt, wherein the compound has a structureaccording to formula II:

or a pharmaceutically acceptable salt, solvate, hydrate, or polymorphthereof, or a solvate, hydrate, or polymorph of the pharmaceuticallyacceptable salt.
 4. The compound according to claim 3, or apharmaceutically acceptable salt, solvate, hydrate, or polymorphthereof, or a solvate, hydrate, or polymorph of the pharmaceuticallyacceptable salt, wherein: each R⁰ is hydrogen; wherein each of R¹ and R²is independently hydrogen or —(CH(R⁶))—O—C(O)R¹⁰; wherein each R⁶ isindependently hydrogen or (C1-C3)alkyl; and wherein each R¹⁰ isindependently selected from the group consisting of —(C1-C6)alkyl,—O—(C1-C6)alkyl, —(C6-C10)aryl, -(4- to 20-membered)heteroalkyl, —O-(4-to 20-membered)heteroalkyl, —[(CH₂)_(y)O]_(z)—R,—CH₂—O—[(CH₂)_(y)O]_(z)—R and —O—[(CH₂)_(y)O]_(z)—R, wherein each ofsaid heteroalkyl independently has 1-6 oxygen atoms, wherein y is aninteger between 1 and 4, wherein z is an integer between 1 and 10,wherein R is hydrogen or (C1-C6)alkyl, and wherein each R¹⁰ isindependently substituted with 0-3 R^(c) groups; wherein R^(c) isselected from the group consisting of halogen, (C1-C3)alkyl, —CN,—O—(C1-C3)alkyl, —S—(C1-C3)alkyl, and —O—C(O)(C1-C3)alkyl; wherein eachR¹² is hydrogen; and wherein each R¹³ is (C1-C3)alkyl.
 5. The compoundaccording to claim 3, or a pharmaceutically acceptable salt, solvate,hydrate, or polymorph thereof, or a solvate, hydrate, or polymorph ofthe pharmaceutically acceptable salt, wherein: each R⁰ is hydrogen;wherein each of R¹ and R² is independently hydrogen,—(CH(R⁶))_(m)—S—C(O)R¹⁰ or —CH₂—(C(R¹¹)₂)—C(O)—CH₂—S—C(O)R¹⁰; whereineach R¹² is hydrogen; wherein each R¹³ is a (C1-C3)alkyl; wherein eachR⁶ is hydrogen; wherein R¹⁰ is selected from the group consisting of(C1-C6)alkyl, and (C6-C10)aryl, wherein each R¹⁰ is substituted with 0-3R^(c); each R¹¹ is independently selected from the group consisting ofhydrogen, —(C1-C6)alkyl, —CH₂—O—C(O)R″ and —C(O)—OR″; each R^(c) is(C1-C3)alkyl or —C(O)O—(C1-C3)alkyl; R″ is hydrogen, (C1-C6)alkyl, or-(4- to 20-membered)heteroalkyl, wherein said heteroalkyl has 1-6 oxygenatoms; and m is an integer selected from the group consisting of 0, 1,2, 3 and
 4. 6. The compound according to claim 1, wherein the compoundhas a structure according to formula III:

or a pharmaceutically acceptable salt, solvate, hydrate, or polymorphthereof, or a solvate, hydrate, or polymorph of the pharmaceuticallyacceptable salt, wherein: R^(a1) and R^(a2) are independently selectedfrom hydrogen, (C1-C6)alkyl, (C6-C10)aryl or a 5- to 10-memberedheteroaryl, wherein said alkyl, aryl and heteroaryl are substituted with0-3 R^(c), provided that at least one of R^(a1) and R^(a2) is(C6-C10)aryl or a 5- to 10-membered heteroaryl; wherein each R^(c) isindependently selected from the group consisting of halogen,(C1-C3)alkyl, —CN, —O—(C1-C3)alkyl, —S—(C1-C3)alkyl,—C(O)O—(C1-C3)alkyl, —N(R′)₂, —CF₃ and —OCF₃; wherein R^(d) is hydrogenor (C1-C3)alkyl; and wherein R^(e1) and R^(e2) are independentlyhydrogen or (C1-C3)alkyl, provided that when R^(a1) is (C6-C10)aryl or a5- to 10-membered heteroaryl, R^(e1) is hydrogen, and that when R^(a2)is (C6-C10)aryl or a 5- to 10-membered heteroaryl, R^(e2) is hydrogen.7. The compound according to claim 6, or a pharmaceutically acceptablesalt, solvate, hydrate, or polymorph thereof, or a solvate, hydrate, orpolymorph of the pharmaceutically acceptable salt wherein: each R⁰ isindependently hydrogen; wherein each R¹² and R¹³ is independentlyselected from the group consisting of hydrogen, —(C1-C3)alkyl,—(C3-C10)cycloalkyl, -(4- to 10-membered)heteroaryl, and -(4- to10-membered)heterocycloalkyl, wherein each of R¹² and R¹³ isindependently substituted with 0-3 R′; wherein R^(a1) and R^(a2) isindependently hydrogen, (C1-C6)alkyl, (C6-C10)aryl or a 5- to10-membered heteroaryl, wherein said alkyl, aryl and heteroaryl aresubstituted with 0-3 R^(c), provided that at least one of R^(a1) andR^(a2) is (C6-C10)aryl or a 5- to 10-membered heteroaryl; wherein R^(c)is selected from the group consisting of hydrogen, halogen,(C1-C3)alkyl, —CN, —O—(C1-C3)alkyl, —S—(C1-C3)alkyl,—C(O)O—(C1-C3)alkyl, —N(R′)₂, —CF₃ and —OCF₃; wherein R^(d) is hydrogenor (C1-C3)alkyl; wherein R^(e1) and R^(e2) are independently hydrogen or(C1-C3)alkyl, provided that when R^(a1) is (C6-C10)aryl or a 5- to10-membered heteroaryl, R^(e1) is hydrogen, and that when R^(a1) is(C6-C10)aryl or a 5- to 10-membered heteroaryl, R^(e2) is hydrogen; andwherein R′ is hydrogen or —(C1-C4)alkyl.
 8. The compound according toclaim 7, or a pharmaceutically acceptable salt, solvate, hydrate, orpolymorph thereof, or a solvate, hydrate, or polymorph of thepharmaceutically acceptable salt, wherein: each R⁰ is hydrogen; whereineach R¹² is hydrogen; wherein each R¹³ is (C1-C3)alkyl; wherein one ofR^(a1) and R^(a2) is (C6-C10)aryl or a 5- to 10-membered heteroaryl, andthe other is hydrogen, wherein said aryl or heteroaryl is substitutedwith 1-3 R^(c); wherein each R^(c) is halogen or (C1-C3)alkyl; andwherein each of R^(d), R^(e1) and R^(e2) is hydrogen.
 9. The compoundaccording to claim 1, wherein the compound has a structure according toformula IV:

or a pharmaceutically acceptable salt, solvate, hydrate, or polymorphthereof, or a solvate, hydrate, or polymorph of the pharmaceuticallyacceptable salt, wherein: R³ is substituted with 0-3 substituentsselected from the group consisting of halogen, oxo, —(C1-C5)alkyl,—O—(C2-C4)alkyl, and —C(O)O(C1-C3)alkyl;
 10. The compound according toclaim 9, or a pharmaceutically acceptable salt, solvate, hydrate, orpolymorph thereof, or a solvate, hydrate, or polymorph of thepharmaceutically acceptable salt, wherein: each R⁰ is independentlyhydrogen or (C1-C3)alkyl; wherein each R¹² and R¹³ is independentlyselected from the group consisting of hydrogen, —(C1-C4)alkyl,—(C3-C10)cycloalkyl, -(4- to 10-membered)heteroaryl, and -(4- to6-membered)heterocycloalkyl, wherein each R¹² and R¹³ is independentlysubstituted with 0-3 R′; wherein R³ is hydrogen, halogen, (C1-C6)alkyl,(C3-C7)cycloalkyl, (5- to 8-membered)heterocycloalkyl, —O—(C1-C6)alkyl,—O—(C3-C7)cycloalkyl, —O-(5- to 8-membered)heterocycloalkyl,(C2-C6)alkenyl, —CH₂OH, phenyl, (5- or 6-membered)heteroaryl, or (5- or6-membered)heterocycloalkyl, wherein R³ is substituted with 0-3substituents selected from the group consisting of halogen, oxo,—(C1-C5)alkyl, —O—(C2-C4)alkyl, and —C(O)O(C1-C3)alkyl; R⁴ is hydrogen,—CN, (C1-C6)alkyl, —O—(C1-C6)alkyl, (C2-C6)alkenyl or —CH₂OH; or R⁴ andR³ are taken together with the carbon atoms to which they are attachedto form a (C5-C6)cycloalkyl, (C6-C10)aryl, (5- to10-membered)heterocycloalkyl or (5- to 10-membered)heteroaryl; R⁵ ishydrogen, halogen, (C1-C6)alkyl or —O—(C1-C6)alkyl; or R⁵ and R⁴ aretaken together with the carbon atoms to which they are attached to forma (C5-C6)cycloalkyl, phenyl, (5- or 6-membered)heterocycloalkyl, or (5-or 6-membered)heteroaryl; R¹⁴ is (C1-C6)alkyl; R¹⁵ is hydrogen,—(C1-C6)alkyl, —CH₂-phenyl, or —CH₂-(5-to 10-membered)heteroaryl,wherein the —(C1-C6)alkyl, —CH2-phenyl, or —CH₂-(5-to10-membered)heteroaryl are substituted with 0-3 substituents selectedfrom the group consisting of —OH, —SH, —SCH₃, —C(O)NH₂, —C(O)OH, —NH₂and —NH—C(═NH)NH₂; R¹⁶ is hydrogen or —(C1-C6)alkyl; and R′ is selectedfrom hydrogen, halogen, (C1-C4)alkyl, or —O—(C1-C4)alkyl.
 11. Thecompound according to claim 10, or a pharmaceutically acceptable salt,solvate, hydrate, or polymorph thereof, or a solvate, hydrate, orpolymorph of the pharmaceutically acceptable salt, wherein: each R⁰ ishydrogen; each R¹² is H; each R¹³ is independently hydrogen or—(C1-C10)alkyl; R³, R⁴ and R⁵ are H; R¹⁴ is (C1-C3)alkyl; R¹⁵ is(C1-C3)alkyl; and R¹⁶ is H.
 12. The compound according to claim 1,wherein the compound has a structure according to formula V:

or a pharmaceutically acceptable salt, solvate, hydrate, or polymorphthereof, or a solvate, hydrate, or polymorph of the pharmaceuticallyacceptable salt, wherein: R′ is halogen, —(C1-C4)alkyl, or—O—(C1-C4)alkyl; and R″ is halogen, —(C1-C6)alkyl or —O—(C2-C6)alkyl.13. The compound according to claim 12, or a pharmaceutically acceptablesalt, solvate, hydrate, or polymorph thereof, or a solvate, hydrate, orpolymorph of the pharmaceutically acceptable salt, wherein: each R⁰ isindependently hydrogen or (C1-C3)alkyl; wherein each R¹² and R¹³ isindependently selected from the group consisting of hydrogen,—(C1-C3)alkyl, —(C3-C10)cycloalkyl, -(4- to 10-membered)heteroaryl, and-(4- to 10-membered)heterocycloalkyl, wherein each R¹² and R^(n) isindependently substituted with 0-3 R′; wherein R⁷ is selected from thegroup consisting of —(C1-C3)alkyl, —(C3-C6)cycloalkyl, and -(4- to6-membered)heterocycloalkyl, wherein R⁷ is substituted with 0-3 R″;wherein R⁸ and R⁹ are independently selected from the group consistingof hydrogen, —(C1-C3)alkyl, —(C3-C6)cycloalkyl, and -(4- to6-membered)heterocycloalkyl, wherein R⁸ and R⁹ are independentlysubstituted with 0-3 R″; wherein R′ is halogen, (C1-C4)alkyl, or—O—(C1-C4)alkyl; and wherein R″ is halogen, —(C1-C3)alkyl or—O—(C1-C3)alkyl.
 14. The compound according to claim 13, or apharmaceutically acceptable salt, solvate, hydrate, or polymorphthereof, or a solvate, hydrate, or polymorph of the pharmaceuticallyacceptable salt, wherein: each R⁰ is hydrogen; each R¹² is H; each R¹³is independently —(C1-C3)alkyl; and R⁷, R⁸ and R⁹ are —(C1-C3)alkyl. 15.The compound according to claim 1, wherein the compound has a structureaccording to formula VI:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,prodrug or double prodrug thereof, or a solvate, hydrate, or polymorphof the pharmaceutically acceptable salt, provided that the compound isnot


16. The compound according to claim 15, or a pharmaceutically acceptablesalt, solvate, hydrate, or polymorph thereof, or a solvate, hydrate, orpolymorph of the pharmaceutically acceptable salt, wherein: each R⁰ isindependently hydrogen, (C1-C3)alkyl, or —SH; each R¹² is independentlyhydrogen, (C1-C3)alkyl or -(4- to 10-membered)heteroaryl; each R¹³ istaken together with the nitrogen atoms to which they are attached toform a (7- to 8-membered)heterocycloalkyl.
 17. The compound according toclaim 1, wherein the compound has a structure according to formula VII:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,prodrug or double prodrug thereof, or a solvate, hydrate, or polymorphof the pharmaceutically acceptable salt, provided that the compound isnot


18. The compound according to claim 17, or a pharmaceutically acceptablesalt, solvate, hydrate, or polymorph thereof, or a solvate, hydrate, orpolymorph of the pharmaceutically acceptable salt, wherein: each R⁰ isindependently hydrogen, (C1-C3)alkyl, or —SH; wherein B is a (6- to8-membered)heterocycloalkyl containing two N atoms, wherein B issubstituted with a (C1-C4)alkyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, so as to form a bicyclic ring, and/or substituted with 0-3(C1-C4)alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,(C1-C6)aryl, (C5 to C6)heteroaryl, (C1-C4)acyl, (C1-C4)alkenyl and(C1-C4)alkynyl, wherein the (C1-C4)alkyl, (C1-C4)alkenyl and(C1-C4)alkynyl are optionally substituted with 1-3 halogen or(C1-C4)alkoxy or B is Moiety B¹; wherein when present, each occurrenceof R¹² and R¹³ is independently hydrogen, —(C1-C6)alkyl, or -(4- to10-membered)heteroaryl.
 19. The compound according to claim 18, or apharmaceutically acceptable salt, solvate, hydrate, or polymorphthereof, or a solvate, hydrate, or polymorph of the pharmaceuticallyacceptable salt, wherein B is the heterocycle

wherein the heterocycle is substituted with a (C1-C4)alkyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, so as to form a bicyclic ring,and/or substituted with 0-3 (C1-C4)alkyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, (C1-C6)aryl, (C5 to C6)heteroaryl, (C1-C4)acyl,(C1-C4)alkenyl and (C1-C4)alkynyl, wherein the (C1-C4)alkyl,(C1-C4)alkenyl and (C1-C4)alkynyl are optionally substituted with 1-3halogen or (C1-C4)alkoxy.
 20. The compound according to claim 1, whereinthe compound is selected from the group consisting of: CompoundStructure 1

PrC-210-PT 2

PrC-210-PT-BzOM 3

PrC-210-PT-POE 4

PrC-210-PT-PivTB 5

PrC-210-PT-POCE 6

PrC-210-PT-POC 7

PrC-210-PT-CIDOxP 8

PrC-210-PT-PyDOxP 9

PrC-210-PT-PivTB2 10

PrC-210-PT-PivTB3 11

PrC-210-PT-PivTB4 12

PrC-210-PivTP 13

DE-PrC-210-PT 14

PrC-210-PT-PEGOE1 15

PrC-210-PT-PEGOE2 16

PrC-210-PT-PEGOE3 17

PrC-210-PT-PEGOE4 18

PrC-210-PT-alaf 18-(S,S)

(S,S)-PrC-210-PT-alaf 18-(R,S)

(R,S)-PrC-210-PT-alaf 19

PrC-210-S-Piv 20

PrC-210-PT-BzTB1 21

2Pip-2PrSH 22

DzCH2SH 23

DMPrC-210 24

[(1R,4s,7S)-2,6-diazabicyclo[5.1.0]octan-4-yl]methanethiol 25

[(1R,4r,7S)-2,6-diazabicyclo[5.1.0]octan-4-yl]methanethiol 26

(1,5-diazocan-3-yl)methanethiol 27

{3,7-diazabicyclo[3.3.1]nonan-1-yl}methanethiol 28

(1-methyl-1,4-diazepan-6-yl)methanethiol 29

[1-(4-fluorobutyl)-1,4-diazepan-6-yl]methanethiol 30

(1-ethyl-1,4-diazepan-6-yl)methanethiol 31

[7-(methoxymethyl)-1,5-diazocan-3-yl]methanethiol 32

[(1R,4S,7S)-2,6-diazabicyclo[5.2.0]nonan-4-yl]methanethiol 33

[(1R,4R,7S)-2,6-diazabicyclo[5.2.0]nonan-4-yl]methanethiol 34

[1-(pyridin-2-yl)-1,4-diazepan-6-yl]methanethiol 35

[(3S,5aR,8aS)-decahydrocyclopenta[b][1,4]diazepin-3- yl]methanethiol 36

[(3R,5aR,8aS)-decahydrocyclopenta[b][1,4]diazepin-3- yl]methanethiol 37

[6-(sulfanylmethyl)-1,4-diazepan-6-yl]methanethiol 38

[(5aR,9aR)-decahydro-1H-1,5-benzodiazepin-3-yl]methanethiol 39

(1,4-diazepan-2-yl)methanethiol 40

(1,4-diazepan-5-yl)methanethiol 41

2-[(2S,5S)-5-methylpiperazin-2-yl]ethane-1-thiol 42

[(3R,8aS)-octahydropyrrolo[1,2-a]pyrazin-3-yl]methanethiol 43

[(2S,5S)-2-methyl-1,4-diazepan-5-yl]methanethiol 44

2-[(2S,5S)-5-(propan-2-yl)piperazin-2-yl]ethane-1-thiol 45

[(2R,5S)-5-ethylpiperazin-2-yl]methanethiol 46

2-[(2S,5S)-4-cyclobutyl-5-methylpiperazin-2-yl]ethane-1-thiol 47

[(2R,5R)-5-methylpiperazin-2-yl]methanethiol 48

[(2S,5S)-2-tert-butyl-1,4-diazepan-5-yl]methanethiol 49

[(2S,5S)-1,2-dimethyl-1,4-diazepan-5-yl]methanethiol 50

[2-((2R,4aS,8aS)-decahydroquinoxalin-2yl)ethane-1-thiol]

or a pharmaceutically acceptable salt, solvate, hydrate, or polymorphthereof, or a solvate, hydrate, or polymorph of the pharmaceuticallyacceptable salt.
 21. A crystalline salt form of a compound according toany one of claims 1-20, or a pharmaceutically acceptable salt, solvate,hydrate, or polymorph thereof or a solvate, hydrate, or polymorph of thepharmaceutically acceptable salt.
 22. The crystalline salt formaccording to claim 21, wherein the salt is selected from the groupconsisting of chloride, benzenesulfonate, 4-toluenesulfonate,cyclohexylsulfamate, fumarate, bromide, maleate, malonate, oxalate,succinate, trifluoroacetate, sulfamate, acetate, ascorbate, mucate,sulfate and 1,5-naphthalenedisulfonate.
 23. The crystalline salt formaccording to any one of claims 21-22, wherein the salt form is stablewhen stored at ambient temperature for at least 1 year.
 24. Apharmaceutical composition comprising a compound according to any one ofclaims 1-20, or the crystalline salt form according to any one of claims21-23 and a pharmaceutically acceptable carrier.
 25. The pharmaceuticalcomposition according to claim 24, wherein the composition furthercomprises an antioxidant.
 26. The pharmaceutical composition accordingto claim 24, wherein the composition is co-administered sequentially,concurrently or separately, with an antioxidant.
 27. The pharmaceuticalcomposition according to claim 24, wherein the Compound is Compound 42or Compound 50, and the composition further comprises an antioxidant.28. The pharmaceutical composition according to any one of claims 25-27,wherein the antioxidant is selected from the group consisting ofascorbic acid, ascorbate, vitamin C, N-acetylcysteine, glutathione,lipoic acid, uric acid, α-tocopherol, β-tocopherol, β-tocopherol,δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol,δ-tocotrienol, vitamin E, carotene, beta-carotene, vitamin A, retinol,selenocysteine, cyanidine-3-glucoside, and ubiquinol.
 29. Thepharmaceutical composition according to any one of claims 25-27, whereinthe antioxidant is a non-thiol antioxidant.
 30. The pharmaceuticalcomposition according to claim 29, wherein the non-thiol antioxidant isselected from the group comprising α-tocopherol, β-tocopherol,γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol,δ-tocotrienol, vitamin E, carotene, beta-carotene, ascorbate, vitamin C,cyanidine-3-glucoside, selenocysteine, or combinations thereof.
 31. Thepharmaceutical composition according to claim 29, wherein the non-thiolantioxidant is selected from the group consisting of α-tocopherol,β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol,γ-tocotrienol, δ-tocotrienol, vitamin E, carotene, beta-carotene,ascorbate, vitamin C, cyanidine-3-glucoside, selenocysteine, andcombinations thereof.
 32. The pharmaceutical composition according toclaim 31, wherein the non-thiol antioxidant is selected from the groupconsisting of α-tocopherol, γ-tocotrienol, and selenocysteine.
 33. Thepharmaceutical composition according to any one of claims 25-32, whereinthe pharmaceutical composition exhibits a synergistic radioprotectiveeffect in mammals, mammalian tissues and/or cultured mammalian cells.34. The pharmaceutical composition according to any one of claims 24-33,wherein the composition is suitable for oral, transmucosal, transdermal,parenteral, topical or cutaneous administration.
 35. The pharmaceuticalcomposition according to claim 34, wherein the composition is suitablefor parenteral administration, and the administration is subcutaneous,intravenous, intramuscular, or intrathecal administration.
 36. Thepharmaceutical composition according to claim 34, wherein thecomposition is suitable for oral administration.
 37. The pharmaceuticalcomposition according to any one of claims 24-36, wherein thecomposition is stable at ambient temperature for at least 1 year.
 38. Amethod of treating or preventing a toxicity or condition associated withionizing radiation exposure in a subject in need thereof, comprisingadministering to said subject a therapeutically effective amount of acompound according to any one of claims 1-20, or a pharmaceuticallyacceptable salt, solvate, hydrate, or polymorph thereof or a solvate,hydrate, or polymorph of the pharmaceutically acceptable salt, or of apharmaceutical composition according to any one of claims 24-37.
 39. Themethod according to claim 38, wherein the source of the ionizingradiation is nuclear warfare, a nuclear reactor, air travel, or spacetravel.
 40. The method according to claim 39, wherein the source of theionizing radiation is space travel, and the radiation is from one ormore of galactic cosmic rays, chronic solar radiation, solar flares orcoronal mass ejections.
 41. The method according to claim 38, whereinthe source of ionizing radiation is radiation therapy.
 42. The method ofany one of claims 38-41, wherein the ionizing radiation exposure isacute radiation exposure.
 43. The method of any one of claims 38-41,wherein the ionizing radiation exposure is chronic radiation exposure.44. The method according to any one of claims 38-43, wherein thesubject's risk of developing future carcinogenesis after exposure toionizing radiation is reduced.
 45. The method according to any one ofclaims 38-44, wherein the toxicity is one or more of bone marrowtoxicity, central nervous system toxicity, immunological toxicity,gastrointestinal toxicity, neurotoxicity, nephrotoxicity, ototoxicity,cardiotoxicity, hepatoxicity, cutaneous toxicity, alopecia mucositis,xerostomia, infertility, peripheral neuropathy, pulmonary toxicity orrenal toxicity.
 46. The method of claim 45, wherein the toxicity is alate onset toxicity.
 47. The method according to any one of claims38-42, wherein the condition is acute radiation syndrome.
 48. The methodaccording to claim 47, wherein one or more symptoms of acute radiationsyndrome is prevented, eliminated or alleviated.
 49. The methodaccording to claim 48, wherein the acute radiation syndrome symptom isone or more symptom selected from the group consisting of nausea,vomiting, headache, diarrhea, loss of appetite, fatigue, fever, skindamage and hair loss.
 50. The method according to any one of claims38-49, wherein the pharmaceutical composition stimulates bone marrowproduction.
 51. The method according to any one of claims 38-43, whereinthe condition is a cognitive disorder selected from Alzheimer's diseaseor dementia.
 52. The method according to any one of claims 38-43,wherein the condition is premature aging.
 53. The method according toany one of claims 38-43, wherein the condition is selected from thegroup consisting of COVID-19-associated cytokine storm,COVID-19-associated multisystem inflammatory syndrome in children(MIS-C), and post-COVID-19 SARS-CoV-2-induced autoimmunity.
 54. Themethod according to any one of claims 38-43, wherein the disease orcondition is associated with oxidative stress.
 55. The method accordingto claim 54, wherein the disease or condition is renal ischemia,myocardial ischemia, spinal cord ischemia and reperfusion injury,Alzheimer's disease, Parkinson's disease, rheumatoid arthritismyocardial infarction, cardiovascular disease, septic shock, chronicinflammation, Friedreich ataxia, Leber's hereditary optic neuropathy,myoclonus epilepsy, ragged red fiber disease, MitochondrialEncephalopathy, Lactic Acidosis and Stroke (MELAS), radiation-inducedcognitive decline, COVID-19-associated cytokine storm,COVID-19-associated multisystem inflammatory syndrome in children(MIS-C), or post-COVID-19 SARS-CoV-2-induced autoimmunity.
 56. Themethod according to any one of claims 38-55, wherein the compound or thepharmaceutical composition is administered prior to, during, or afterthe subject has been or will be exposed to ionizing radiation.
 57. Amethod of protecting normal tissues in a subject against toxicitiesassociated with radiation therapy with minimal effect on the tumorresponse to those treatments, the method comprising administering tosaid subject a therapeutically effective amount of a compound accordingto any one of claims 1-20, or a pharmaceutically acceptable salt,solvate, hydrate, or polymorph thereof or a solvate, hydrate, orpolymorph of the pharmaceutically acceptable salt, or of apharmaceutical composition according to any one of claims 24-37.
 58. Themethod according to claim 57, wherein the radiation therapy is gammaradiation, X-radiation, proton beam radiation, electron beam radiation,gamma radiation from cobalt-60 decay, or in the form of aradiopharmaceutical.
 59. The method according to claim 57 or 58, whereinthe compound or the pharmaceutical composition is administered before,concurrently, separately, sequentially with, or after a radiationtherapy.
 60. The method according to any one of claims 57-59, whereinthe radiation therapy is combined with a chemotherapeutic agent orimmunotherapy.
 61. The method according to claim 60, wherein theimmunotherapy is selected from the group consisting of immune checkpointinhibitors, T-cell transfer therapy, monoclonal antibodies, treatmentvaccines and immune system modulators.
 62. The method according to claimor 60, wherein the chemotherapeutic agent is selected fromcyclophosphamide, ifosfamide, etoposide, oxaliplatin, cisplatin,carboplatin, mechlorethamine, melphalan, chlorambucil, cyclophosphamide,streptozocin, carmustine, lomustine, bleomycin, busulfan, bendamustine,dacarbazine, doxorubicin, daunoubicin, temozolomide, thiotepa,altretamine, procarbaine, hexamethylmelamine, teniposide ormitoxantrone.
 63. A method of protecting normal tissues in a subjectagainst toxicities associated with chemotherapy without adverselyaffecting the tumor response to those treatments, the method comprisingadministering to said subject a therapeutically effective amount of acompound according to any one of claims 1-20, or a pharmaceuticallyacceptable salt, solvate, hydrate, or polymorph thereof or a solvate,hydrate, or polymorph of the pharmaceutically acceptable salt, or of apharmaceutical composition according to any one of claims 24-37.
 64. Themethod according to claim 63, wherein the chemotherapeutic agent isselected from cyclophosphamide, ifosfamide, etoposide, oxaliplatin,cisplatin, carboplatin, mechlorethamine, melphalan, chlorambucil,cyclophosphamide, streptozocin, carmustine, lomustine, bleomycin,busulfan, bendamustine, dacarbazine, doxorubicin, daunoubicin,temozolomide, thiotepa, altretamine, procarbaine, hexamethylmelamine,teniposide or mitoxantrone.
 65. The method according to claim 63 or 64,wherein the compound or the pharmaceutical composition is administeredbefore, concurrently, separately, sequentially with, or after achemotherapeutic agent.
 66. The method according to any of claims 63-65,wherein the chemotherapy is combined with immunotherapy.
 67. The methodaccording to claim 66, wherein the immunotherapy is selected from thegroup consisting of immune checkpoint inhibitors, T-cell transfertherapy, monoclonal antibodies, treatment vaccines and immune systemmodulators.
 68. A method of reducing the risk of secondary tumorinduction in a subject being treated with radiation therapy, the methodcomprising administering to said subject a therapeutically effectiveamount of a compound according to any one of claims 1-20, or apharmaceutically acceptable salt, solvate, hydrate, or polymorph thereofor a solvate, hydrate, or polymorph of the pharmaceutically acceptablesalt, or of a pharmaceutical composition according to any one of claims24-37.
 69. The method according to claim 68, wherein the radiationtherapy is gamma radiation, X-radiation, proton beam radiation or gammaradiation from cobalt-60 decay, or from a radiopharmaceutical.
 70. Themethod according to claim 68 or 69, wherein the compound or thepharmaceutical composition is administered before, concurrently,separately, sequentially with, or after a radiation therapy.
 71. Themethod according to any one of claims 68-70, wherein the radiationtherapy is combined with a chemotherapeutic agent or immunotherapy. 72.The method according to claim 71, wherein the immunotherapy is selectedfrom the group consisting of immune checkpoint inhibitors, T-celltransfer therapy, monoclonal antibodies, treatment vaccines and immunesystem modulators.
 73. The method according to claim or 71, wherein thechemotherapeutic agent is selected from cyclophosphamide, ifosfamide,etoposide, oxaliplatin, cisplatin, carboplatin, mechlorethamine,melphalan, chlorambucil, cyclophosphamide, streptozocin, carmustine,lomustine, bleomycin, busulfan, bendamustine, dacarbazine, doxorubicin,daunoubicin, temozolomide, thiotepa, altretamine, procarbaine,hexamethylmelamine, teniposide or mitoxantrone.
 74. A method of reducingthe risk of secondary tumor induction in a subject being treated withchemotherapy, the method comprising administering to said subject atherapeutically effective amount of a compound according to any one ofclaims 1-20, or a pharmaceutically acceptable salt, solvate, hydrate, orpolymorph thereof or a solvate, hydrate, or polymorph of thepharmaceutically acceptable salt, or of a pharmaceutical compositionaccording to any one of claims 24-37.
 75. The method according to claim74, wherein the chemotherapeutic agent is selected fromcyclophosphamide, ifosfamide, etoposide, oxaliplatin, cisplatin,carboplatin, mechlorethamine, melphalan, chlorambucil, cyclophosphamide,streptozocin, carmustine, lomustine, bleomycin, busulfan, bendamustine,dacarbazine, doxorubicin, daunoubicin, temozolomide, thiotepa,altretamine, procarbaine, hexamethylmelamine, teniposide ormitoxantrone.
 76. The method according to claim 74 or 75, wherein thecompound or the pharmaceutical composition is administered before,concurrently, separately, sequentially, or after with a chemotherapeuticagent.
 77. The method according to any of claims 74-76, wherein thechemotherapy is combined with immunotherapy.
 78. The method according toclaim 77, wherein the immunotherapy is selected from the groupconsisting of immune checkpoint inhibitors, T-cell transfer therapy,monoclonal antibodies, treatment vaccines and immune system modulators.79. The method of any one of claim 38 or 57-78, wherein the subject hascancer and the cancer is hematological cancer, bone cancer, leukemia,lymphoma, myeloma, rectal cancer, colorectal cancer, breast cancer,ovarian cancer, prostate cancer, androgen-dependent prostate cancer,lung cancer, mesothelioma, head and neck cancer, esophageal cancer,gastric cancer, pancreatic cancer, gastrointestinal cancer, renal cellcancer, testicular cancer, germ cell cancer, glioma, cancers of thecentral nervous system or any other primary or solid tumor.
 80. A methodof reducing the risk of tumor induction in a subject who has beenexposed to, is being exposed to, or will be exposed to ionizingradiation, the method comprising administering to said subject atherapeutically effective amount of a compound according to any one ofclaims 1-20, or a pharmaceutically acceptable salt, solvate, hydrate,polymorph or combination thereof, or of a pharmaceutical compositionaccording to any one of claims 24-37.
 81. The method according to claim80, wherein the source of the ionizing radiation is nuclear warfare, anuclear reactor, air travel, or space travel.
 82. The method accordingto claim 81, wherein the source of the ionizing radiation is spacetravel, and the radiation is from one or more of galactic cosmic rays,chronic solar radiation, solar flares or coronal mass ejections.
 83. Themethod according to claim 80, wherein the source of ionizing radiationis radiation therapy.
 84. The method of any one of claims 80-83, whereinthe ionizing radiation exposure is acute radiation exposure.
 85. Themethod of any one of claim 80-83, wherein the ionizing radiationexposure is chronic radiation exposure.
 86. A method of slowing theaging process in a subject, wherein the method comprises administering acompound according to any one of claims 1-20, or the pharmaceuticalcomposition according to any one of claims 24-37.
 87. The methodaccording to claim 86, wherein the health span of the subject isincreased.
 88. A method of treating a disease or condition in a subjectin need thereof comprising administering a compound according to any oneof claims 1-20, or the pharmaceutical composition according to any oneof claims 24-37.
 89. The method according to claim 88, wherein thedisease or condition is associated with oxidative stress.
 90. The methodaccording to claim 88 or 89, wherein the disease or condition is renalischemia, myocardial ischemia, spinal cord ischemia and reperfusioninjury, Alzheimer's disease, Parkinson's disease, rheumatoid arthritismyocardial infarction, cardiovascular disease, septic shock, chronicinflammation, Friedreich ataxia, Leber's hereditary optic neuropathy,myoclonus epilepsy, ragged red fiber disease, MitochondrialEncephalopathy, Lactic Acidosis and Stroke (MELAS), radiation-inducedcognitive decline, COVID-19-associated cytokine storm,COVID-19-associated multisystem inflammatory syndrome in children(MIS-C), or post-COVID-19 SARS-CoV-2-induced autoimmunity.